BR112019012589B1 - COMPOUNDS AND PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OF CANCER BY INHIBITING ARGINASE ACTIVITY AND PROCESS FOR THE PRODUCTION OF THE COMPOUND - Google Patents

Abstract

The description relates to a new class of compounds that exhibit inhibitory activity towards arginase and pharmaceutical compositions comprising the compounds of the description. Also provided herein are methods of treating cancer with the arginase inhibitors of the description.

Description

Background

[0001] Cancer is characterized by the uncontrolled growth of cells in the body, inducing the invasion of essential organs and often, death. Initially, pharmacological treatment of cancer used non-specific cytotoxic agents that targeted all rapidly dividing cells, including normal cells. These nonspecific cytotoxic agents have antitumor effects, but their use is often limited by severe toxicities. As our understanding of the proteins and pathways that allow cancer cells to grow has evolved, newer, more specific agents have been developed that block the specific proteins that are activated in cancer cells.

[0002] As an emerging field for the development of therapeutics that address the challenges presented in the treatment of cancers is immuno-oncology, also referred to as tumor immunology. Certain types of tumor have evolved mechanisms to evade destruction by the body's immune system. Tumor immunology is a therapeutic area focused on activating the body's own immune system to attack and kill tumors. The naturally occurring amino acid, arginine, is implicated in tumor immunology as it is important for the activation, growth and survival of the body's fighting cytotoxic T cells. However, arginine levels are reduced in the tumor microenvironment by arginase, an enzyme produced and secreted by neutrophils and myeloid-derived suppressor cells (MDSCs) that accumulate in cancer patients of multiple histotypes. Indeed, elevated levels of arginase enzyme have been observed in the plasma of patients with renal cell carcinoma, breast cancer, chronic myelogenous leukemia, esophageal cancer, prostate cancer, non-small cell lung cancer, glioblastoma, and acute myeloid leukemia. Therefore, there is a need to develop arginase inhibitors that restore arginine levels in the tumor microenvironment, thereby promoting the tumor suppressing activity of cytotoxic T cells.

Description Summary

ou um sal farmaceuticamente aceitável dos mesmos; em que Rb, X, R1, R2, R3 e R4 são definidos como estabelecido na descrição detalhada da seção de descrição, abaixo.[0003] In certain embodiments, the description relates to a series of compounds useful for arginase inhibition. The compounds of the description have a structure of formula (I):

or a pharmaceutically acceptable salt thereof; wherein Rb, X, R1, R2, R3 and R4 are defined as set forth in the detailed description in the description section below.

nos compostos de fórmula (I) representa um resíduo de alfa-aminoácido, em que X = O e a amina terminal é opcionalmente substituída com R3. Em tais modalidades, o grupo R1 é uma cadeia lateral de alfa- aminoácido. As cadeias laterais de aminoácido adequadas incluem aquelas de aminoácidos de°Corrência natural e não natural. Por exemplo, em algumas modalidades R1 é uma cadeia lateral de aminoácido de Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Ala, Val, Ile, Leu, Met, Phe, Tyr, ou Trp, em particular de Gly, Ser, ou Ala. Em certas modalidades, R1 é uma cadeia lateral de aminoácido de Gly, Ala, ou Ser.[0004] In certain arrangements, the structure

in compounds of formula (I) it represents an alpha-amino acid residue, where X = O and the terminal amine is optionally substituted with R3. In such embodiments, the R1 group is an alpha-amino acid side chain. Suitable amino acid side chains include those of naturally occurring and non-naturally occurring amino acids. For example, in some embodiments R1 is an amino acid side chain of Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Ala, Val, Ile, Leu, Met, Phe, Tyr, or Trp, in particular from Gly, Ser, or Ala. In certain embodiments, R1 is an amino acid side chain of Gly, Ala, or Ser.

[0005] In such modes, R1 can adopt the R- or S- configuration.

[0006] In certain embodiments, the description also relates to pharmaceutical compositions comprising a compound of the description and a pharmaceutically acceptable carrier.

[0007] In certain embodiments, the disclosure relates to methods of treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the disclosure.

[0008] The description also relates to methods for treating or preventing cancer, comprising conjointly administering to a subject in need thereof an arginase inhibitor of the description and one or more additional chemotherapeutic agents.

[0009] In particular embodiments, the disclosure relates to methods for treating or preventing cancer, comprising jointly administering to a subject in need thereof an arginase inhibitor of the invention and an indoleamine 2,3-dioxygenase (IDO) inhibitor . The IDO inhibitor can be a compound described in, or a compound having a structure of any of the formulas described herein. In particular embodiments, the IDO inhibitor is epacadostat.

Brief Description of the Drawings

[00010] FIG. 1 shows the structure of compound 10e obtained by X-ray diffraction at 50% thermal ellipsoid probability levels. Most hydrogen atoms have been omitted for clarity.

[00011] FIG. 2 shows NMR spectra (in D 2 O) showing the conversion of compound 10 (referred to as compound A in the figure) to compound 10e (referred to as compound B in the figure) and back to compound 10 (referred to as compound C in the figure).

[00012] FIG. 3 is a graph depicting tumor volume over time. Arginase 10 inhibitor compound, administered as a single agent, decreases tumor growth relative to control in C57BL/6 mice implanted with Lewis Lung Carcinoma cells.

[00013] FIG. 4 is a graph depicting tumor volume over time. Madison109 murine lung carcinoma cells were implanted into BALB/c mice and mice were orally dosed with vehicle or arginase inhibitor compound 10 BID (N=10 per group).

[00014] FIG. 5 is a graph depicting tumor volume over time. B16F10 murine melanoma cells were implanted into C57BL/6 mice and the mice were orally dosed with vehicle or arginase inhibitor compound 10 BID (N=10 per group).

[00015] FIG. 6A and FIG. 6B depict the growth of 4T1 mammary carcinoma cells orthotopically implanted in vehicle-treated female BALB/c mice; compound 10 (100 mg/kg PO BID); anti-CTLA-4 (5 mg/kg IP on days 2, 5, 8) plus anti-PD-1 (5 mg/kg IP on days 3, 6, and 9); or the combination of Compound 10 with anti-CTLA-4 and anti-PD-1 (N = 10 per group; *P < 0.05; ***P < 0.001, **** P < 0.0001 vs vehicle ).

[00016] FIG. 7 is a plot of the sorption isotherm of compound 10e.

Detailed Description of the Invention

[00017] The present description refers to the compounds and compositions useful for the inhibition of arginase, as well as to various therapeutic applications thereof. The inventors' previous studies have focused on a class of small molecules having (i) amino acid-like moieties (ii) boronic acid, such as the compounds generally represented by Formula A, below. Compounds of Formula A have been found to be useful in inhibiting arginase.

[00018] Surprisingly, the inventors discovered that when a free base compound of Formula A was treated with an anhydrous alcohol, a cyclic alkoxylated compound of formula (I) could be isolated. Unlike many drugs, such cyclic alkoxylated compounds of formula (I) do not require an enzymatic process to reveal the underlying arginase inhibitor compounds; on the contrary, exposure of a compound of formula (I) to water or an aqueous environment (e.g., in oral dosing) will generate the "underlying" arginase inhibitor, e.g., the compound of formula (A). Typically, these cyclic alkoxylated compounds of formula (I) exhibit improved processing and handling properties, high purity, and better stability compared to non-cyclized counterparts.

Compounds of the description

ou um sal farmaceuticamente aceitável do mesmo; em que as definições de Rb, X, R1, R2, R3 e R4 são definidas abaixo[00019] Consequently, the description refers to a compound having a structure of formula (I):

or a pharmaceutically acceptable salt thereof; where the definitions of Rb, X, R1, R2, R3 and R4 are defined below

ou um sal farmaceuticamente aceitável do mesmo; em que: Rb é selecionado de H, alquila, alquenila, alquinila, acila, - C(O)O(alquila), e -C(O)O(arila); X é O ou S; R1 e R2 são cada qual independentemente selecionado de H, alquila, -CH2OH, alquenila, alquinila, cicloalquila, (cicloalquil)alquila, hetero-cicloalquila, (heterocicloalquil)alquila, arila, heteroarila, aralquila, e heteroaralquila; ou R1 e R2 são considerados juntamente com os átomos intervenientes para formar um anel de 3 a 7 membros; e R3 é H ou alquila; ou R1 e R3 são considerados juntamente com os átomos intervenientes para formar um anel de 5 a 7 membros; e R4 é H ou (C1-C6)alquila.[00020] In certain embodiments, the description refers to a compound having a structure of formula (I'):

or a pharmaceutically acceptable salt thereof; wherein: Rb is selected from H, alkyl, alkenyl, alkynyl, acyl, -C(O)O(alkyl), and -C(O)O(aryl); X is O or S; R1 and R2 are each independently selected from H, alkyl, -CH2OH, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; or R1 and R2 are taken together with the intervening atoms to form a 3- to 7-membered ring; and R3 is H or alkyl; or R1 and R3 are taken together with the intervening atoms to form a 5- to 7-membered ring; and R4 is H or (C1-C6)alkyl.

[00021] In certain embodiments of the compound of formula I', R2 is H.

[00022] In certain embodiments of the compound of formula I', Rb is H or alkyl. In particular embodiments, Rb is H.

[00023] In certain embodiments of the compound of formula I', X is O.

[00024] In certain embodiments of the compound of formula I', if R1 is H, then R3 will not be benzyl.

[00025] In certain embodiments of the compound of formula I', R1 is H. In some such embodiments R2 is H.

[00026] In certain embodiments of the compound of formula I', if R1 is benzyl, then R3 will not be methyl.

[00027] In certain embodiments of the compound of formula I', R1 is aralkyl, heteroaralkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl.

[00028] In certain embodiments of the compound of formula I', R1 is aralkyl or heteroaralkyl.

[00029] In certain embodiments of the compound of formula I', R1 is benzyl.

[00030] In certain embodiments of the compound of formula I', R1 is not benzyl substituted by -CF3.

[00031] In certain embodiments of the compound of formula I', R1 is heteroaralkyl. In particular embodiments R1 is -CH2-(1H-imidazol-4-yl).

[00032] In certain embodiments of the compound of formula I', R1 is alkyl, alkenyl, or alkynyl.

[00033] In certain embodiments of the compound of formula I', R1 is (C1-C4)alkyl. In some such embodiments, R2 is H.

[00034] In certain embodiments of the compound of formula I', R1 is methyl. In some such embodiments, R2 is H.

[00035] In certain embodiments of the compound of formula I', R1 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[00036] In certain embodiments of the compound of formula I', R1 is -CH2OH. In some such embodiments, R2 is H.

[00037] In certain embodiments, both R1 and R2 are hydrogen.

[00038] In certain embodiments of the compound of formula I', R1 and R2 are taken together with the intervening atoms to form a 5- to 7-membered ring.

[00039] In certain embodiments of the compound of formula I', R3 is H.

[00040] In certain embodiments of the compound of formula I', R1 and R3 are taken together with the intervening atoms to form a 5-membered ring.

[00041] In certain embodiments of the compound of formula I', R1 and R3 taken together with the intervening atoms do not form a 5-membered ring.

[00042] In certain embodiments of the compound of formula I', R1 and R3 are taken together with the intervening atoms to form a 6- or 7-membered ring.

[00043] In certain embodiments of the compound of formula I', R1 and R3, taken together with the intervening atoms, do not form a tetrahydroisoquinolinyl ring, for example, .

[00044] In certain embodiments of the compound of formula I', R4 is (C1-C4)alkyl. In particular embodiments, the lower alkyl group is selected from methyl, ethyl, propyl, isopropyl and isobutyl. In particular embodiments, R4 is ethyl. In other particular embodiments, R4 is isopropyl.

ou um sal farmaceuticamente aceitável do mesmo; em que: Rb é H ou é selecionado de alquila, alquenila, alquinila, acila opcionalmente substituída, -C(O)O(alquila), e -C(O)O(arila); X é O ou S; R1 e R2 são cada qual independentemente selecionado de H e alquila, alquenila, alquinila, cicloalquila, (cicloalquil)alquila, hetero- cicloalquila, (heterocicloalquil)alquila, arila, heteroarila, aralquila, e heteroaralquila opcionalmente substituída; ou R1 e R2 são considerados juntamente com os átomos intervenientes para formar um anel de 3 a 7 membros opcionalmente substituído; e R3 é H ou alquila opcionalmente substituída; ou R1 e R3 são considerados juntamente com os átomos intervenientes para formar um anel de 5- a 7- opcionalmente substituído; e R4 é H ou (C1-C6)alquila.[00045] In certain embodiments, the description refers to a compound having a structure of formula (I''):

or a pharmaceutically acceptable salt thereof; wherein: Rb is H or is selected from alkyl, alkenyl, alkynyl, optionally substituted acyl, -C(O)O(alkyl), and -C(O)O(aryl); X is O or S; R1 and R2 are each independently selected from H and alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, aralkyl, and optionally substituted heteroaralkyl; or R1 and R2 are taken together with the intervening atoms to form an optionally substituted 3- to 7-membered ring; and R3 is H or optionally substituted alkyl; or R1 and R3 are taken together with the intervening atoms to form an optionally substituted 5- to 7- ring; and R4 is H or (C1-C6)alkyl.

ou um sal farmaceuticamente aceitável do mesmo; em que: Rb é H ou é um grupo selecionado de alquila, alquenila, alquinila, acila, -C(O)O(alquila), e -C(O)O(arila), em que o referido grupo é opcionalmente substituído por um ou mais substituintes selecionados de hidróxi, halo, haloalquila, alcóxi, -SH, -S-(alquila), - SeH, -Se-(alquila), arila, heteroarila, cicloalquila, hetero-cicloalquila, amino, ácido carboxílico, éster, guanidino, e amido; X é O ou S; R1 e R2 são cada qual independentemente selecionado de H ou um grupo selecionado de alquila, alquenila, alquinila, cicloalquila, (cicloalquil)alquila, hetero-cicloalquila, (heterocicloalquil)alquila, arila, heteroarila, aralquila, e heteroaralquila, em que o referido grupo é opcionalmente substituído por um ou mais substituintes selecionados de hidróxi, halo, haloalquila, alcóxi, -SH, -S-(alquila), -SeH, -Se- (alquila), arila, heteroarila, cicloalquila, hetero-cicloalquila, amino, ácido carboxílico, éster, guanidino, e amido; ou R1 e R2 são considerados juntamente com os átomos intervenientes para formar um anel de 3 a 7 membros, em que o anel de 3 a 7 membros é opcionalmente substituído com um ou mais substituintes selecionados de hidróxi, halo, haloalquila, alcóxi, -SH, -S- (alquila), -SeH, -Se-(alquila), arila, heteroarila, cicloalquila, hetero- cicloalquila, amino, ácido carboxílico, éster, guanidino, e amido; e R3 é H ou alquila opcionalmente substituída com um ou mais substituintes selecionados de hidróxi, halo, haloalquila, alcóxi, - SH, -S-(alquila), -SeH, -Se-(alquila), arila, heteroarila, cicloalquila, hetero-cicloalquila, amino, ácido carboxílico, éster, guanidino, e amido; ou R1 e R3 são considerados juntamente com os átomos intervenientes para formar um anel de 5 a 7 membros, em que o anel de 5 a 7 membros é opcionalmente substituído com um ou mais substituintes selecionados de hidróxi, halo, haloalquila, alcóxi, -SH, -S- (alquila), -SeH, -Se-(alquila), arila, heteroarila, cicloalquila, hetero- cicloalquila, amino, ácido carboxílico, éster, guanidino, e amido; e R4 é H ou (C1-C6)alquila.[00046] In certain embodiments, the description refers to a compound having a structure of formula (I"'):

or a pharmaceutically acceptable salt thereof; wherein: Rb is H or is a group selected from alkyl, alkenyl, alkynyl, acyl, -C(O)O(alkyl), and -C(O)O(aryl), wherein said group is optionally substituted by one or more substituents selected from hydroxy, halo, haloalkyl, alkoxy, -SH, -S-(alkyl), -SeH, -Se-(alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester , guanidino, and starch; X is O or S; R1 and R2 are each independently selected from H or a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, wherein said group is optionally substituted by one or more substituents selected from hydroxy, halo, haloalkyl, alkoxy, -SH, -S-(alkyl), -SeH, -Se- (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino , carboxylic acid, ester, guanidino, and starch; or R1 and R2 are taken together with the intervening atoms to form a 3- to 7-membered ring, wherein the 3- to 7-membered ring is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, alkoxy, -SH , -S- (alkyl), -SeH, -Se- (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino, and amido; and R3 is H or alkyl optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, alkoxy, -SH, -S-(alkyl), -SeH, -Se-(alkyl), aryl, heteroaryl, cycloalkyl, hetero -cycloalkyl, amino, carboxylic acid, ester, guanidino, and starch; or R1 and R3 are taken together with the intervening atoms to form a 5- to 7-membered ring, wherein the 5- to 7-membered ring is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, alkoxy, -SH , -S- (alkyl), -SeH, -Se- (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino, and amido; and R4 is H or (C1-C6)alkyl.

[00047] In certain embodiments of the compound of formula I"', R2 is H.

[00048] In certain embodiments of the compound of formula I"', Rb is H or alkyl. In particular embodiments, Rb is H.

[00049] In certain embodiments of the compound of formula I"', X is O.

[00050] In certain embodiments of the compound of formula I", if R1 is H, then R3 will not be benzyl.

[00051] In certain embodiments of the compound of formula I"', R1 is H.

[00052] In some such embodiments R2 is H.

[00053] In certain embodiments of the compound of formula I", if R1 is benzyl, then R3 will not be methyl.

[00054] In certain embodiments of the compound of formula I"', R1 is aralkyl, heteroaralkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl.

[00055] In certain embodiments of the compound of formula I"', R1 is aralkyl or heteroaralkyl.

[00056] In certain embodiments of the compound of formula I"', R1 is benzyl.

[00057] In certain embodiments of the compound of formula I"', R1 is not benzyl substituted by -CF3.

[00058] In certain embodiments of the compound of formula I"', R1 is heteroaralkyl. In particular embodiments R1 is -CH2-(1H-imidazol-4-yl).

[00059] In certain embodiments of the compound of formula I"', R1 is alkyl, alkenyl, or alkynyl.

[00060] In certain embodiments of the compound of formula I"' R1 is alkyl optionally substituted by one or more substituents independently selected from hydroxy, alkoxy, haloalkyl, and -S-(alkyl).

[00061] In certain embodiments of the compound of formula I"', R1 is (C1-C4)alkyl. In some such embodiments, R2 is H.

[00062] In certain embodiments of the compound of formula I"', R1 is methyl. In some such embodiments, R2 is H.

[00063] In certain embodiments of the compound of formula I', R1 is -CH2OH. In some such embodiments, R2 is H.

[00064] In certain embodiments of the compound of formula I"', R1 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some such embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from hydroxy, halo, haloalkyl, alkoxy, -SH, and -S- (alkyl).

[00065] In certain embodiments of the compound of formula I"', R1 is -CH2OH. In some such embodiments, R2 is H.

[00066] In certain embodiments the compound of formula I"', R1 is an amino acid side chain of Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Ala, Val, Ile, Leu, Met, Phe, Tyr, or Trp.

[00067] In certain embodiments of the compound of formula I"', R1 and R2 are taken together with the intervening atoms to form a 5- to 7-membered ring.

[00068] In certain embodiments of the compound of formula I"', R3 is H.

[00069] In certain embodiments of the compound of formula I"', R1 and R3 are taken together with the intervening atoms to form a 5-membered ring.

[00070] In certain embodiments of the compound of formula I"', R1 and R3 taken together with the intervening atoms do not form a 5-membered ring.

[00071] In certain embodiments of the compound of formula I"', R1 and R3 are taken together with the intervening atoms to form a 6- or 7-membered ring.

[00072] In certain embodiments of the compound of formula I"', R1 and R3, taken together with the intervening atoms, do not form a tetrahydroisoquinolinyl ring, for example, .

[00073] In certain embodiments of the compound of formula I"', R4 is (C1-C4)alkyl. In particular embodiments the lower alkyl group is selected from methyl, ethyl, propyl, isopropyl and isobutyl. In particular embodiments, R4 is ethyl In other particular embodiments, R4 is isopropyl.

x ou um sal farmaceuticamente aceitável do mesmo; em que: R1 é selecionado de H ou um grupo selecionado de alquila, alquenila, alquinila, cicloalquila, (cicloalquil)alquila, hetero-cicloalquila, (heterocicloalquil)alquila, arila, heteroarila, aralquila, e heteroaralquila, em que o referido grupo é opcionalmente substituído por um ou mais substituintes selecionados de hidróxi, halo, haloalquila, alcóxi, -SH, -S- (alquila), -SeH, -Se-(alquila), arila, heteroarila, cicloalquila, hetero- cicloalquila, amino, ácido carboxílico, éster, guanidino, e amido; e R4 é H ou (C1-C6)alquila.[00074] In certain embodiments, the description refers to a compound having a structure of formula (I*):

x or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from H or a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, wherein said group is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, alkoxy, -SH, -S- (alkyl), -SeH, -Se- (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, acid carboxylic, ester, guanidino, and starch; and R4 is H or (C1-C6)alkyl.

[00075] In certain embodiments of the compound of formula I*, R1 is aralkyl, heteroaralkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl.

[00076] In certain embodiments of the compound of formula I*, R1 is aralkyl or heteroaralkyl.

[00077] In certain embodiments of the compound of formula I*, R1 is benzyl.

[00078] In certain embodiments of the compound of formula I*, R1 is not benzyl substituted by -CF3.

[00079] In certain embodiments of the compound of formula I*, R1 is heteroaralkyl. In particular embodiments R1 is -CH2-(1H-imidazol-4-yl).

[00080] In certain embodiments of the compound of formula I*, R1 is alkyl, alkenyl, or alkynyl.

[00081] In certain embodiments of the compound of formula I*, R1 is alkyl optionally substituted by one or more substituents independently selected from hydroxy, alkoxy, haloalkyl, and -S- (alkyl).

[00082] In certain embodiments of the compound of formula I*, R1 is (C1-C4)alkyl. In certain embodiments of the compound of formula I*, R1 is methyl.

[00083] In certain embodiments of the compound of formula I*, R1 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some such embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted with one or more groups selected from hydroxy, halo, haloalkyl, alkoxy, -SH, and -S-(alkyl).

[00084] In certain embodiments of the compound of formula I*, R1 is -CH2OH.

[00085] In certain embodiments, the compound of formula I*, R1 is an amino acid side chain of Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Ala, Val, Ile , Leu, Met, Phe, Tyr, or Trp.

[00086] In certain embodiments of the compound of formula I*, R4 is (C1-C4)alkyl. In particular embodiments the lower alkyl group is selected from methyl, ethyl, propyl, isopropyl and isobutyl. In particular embodiments, R4 is ethyl. In other particular embodiments, R4 is isopropyl.

[00087] In a particular embodiment, the compound of formula I* has the following structure:

[00088] The compound may be a free base or may be ionized to form a pharmaceutically acceptable salt thereof.

[00089] In another particular embodiment, the compound of formula I* has the following structure:

[00090] The compound may be a free base or may be ionized to form a pharmaceutically acceptable salt thereof.

[00091] In another particular embodiment, the compound of formula I* has the following structure:

[00092] The compound may be a free base or may be ionized to form a pharmaceutically acceptable salt thereof.

[00093] In another particular embodiment, the compound of formula I* has the following structure:

[00094] The compound may be a free base or may be ionized to form a pharmaceutically acceptable salt thereof.

[00095] In another particular embodiment, the compound of formula I* has the following structure:

[00096] The compound may be a free base or may be ionized to form a pharmaceutically acceptable salt thereof.

[00097] In another particular embodiment, the compound of formula I* has the following structure:

[00098] The compound may be a free base or may be ionized to form a pharmaceutically acceptable salt thereof.

[00099] In certain embodiments, the compound of formula (I) has a structure of formula (Ia):

[000100] In certain embodiments, the compound of formula (I) has a structure of formula (Ib):

[000101] In certain embodiments, the compound of formula (I) has a structure of formula (Ic):

[000102] In certain embodiments, the compound of formula (I) has a structure of formula (Id):

[000103] In certain embodiments, the compound of formula (I) has the structure of formula (Ie):

[000104] In certain embodiments, the compound of formula (I) has a structure of formula (If):

[000105] In certain embodiments, the compound of formula (I) has a structure of formula (Ig):

[000106] In certain embodiments, the compound of formula (I) has a structure of formula (Ih):

[000107] For compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih), the variables Rb, X, R1, R2, R3 and R4 are as described above for the various formulas included in formula (I).

[000108] It will be understood that any recitation of the compound of formula (I) in the description below will include the compounds of formulas (I'), (I''), (I"'), (I*), (Ia), ( Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih).

[000109] Related arginase inhibitors are described in US Patent Application Publications Nos. 2014/0343019, 2012/0083469, 2014/0371175, 2012/0129806, 2015/0080341, and PCT Application Publications No. WO 99/19295, WO 2010/085797, and WO 2012/091757, which are hereby incorporated by reference herein in their entirety. Such related arginase inhibitors are expected to form cyclic alkoxylated compounds similar to the disclosed compounds when they are treated with an anhydrous alcohol. In some embodiments, an anhydrous alcohol comprises 1 to 5% water, preferably <1% water, more preferably <0.5% water.

Formula J ; em que: R2 é selecionado de H, (C1-C6) alquila linear ou ramificada, e (Ci-Cβ)alquil-C(O)-; W, X, Y, e Z são cada qual independentemente selecionado de -C(R')(R'")-, -C(R"')2-, -CR"'-, -NR'"-, -N-, -O-, -C(O)-, e -S-, em que não mais do que três de W, X, Y, e Z simultaneamente representam uma ligação; pelo menos um de W, X, Y, ou Z é selecionado de -NR'"-, -N-, -O-, e -S-; e não mais do que dois membros adjacentes de W, X, Y, e Z são simultaneamente -O-, -S-, -N-, ou -NR'"-; 1, m, n e p são cada qual independentemente 0 ou 1 ou 2;

opcionalmente representa uma ou mais ligações duplas; D é selecionado de (C3-C5)alquileno linear ou ramificado; R', R" e R'" são cada qual independentemente selecionado de H, OH, S(O)Rd, S(O)2Rd, (C1-Cs)alquila, (C3-C6)arila, -NH2, -NH(C1-C6) alquila, -N[(C1-C6)alquil]2, -C(O)NRdRe, -C(O)(C1-C6)alquila, -C(O)(C3-C14) arila, -C(O)O(C1-C6)alquila, -C(O)O(C3-C14)arila, (C3-C6)cicloalquila, (C3-C14)hetero-cicloalquila, -C(O)(C3-C14)hetero-cicloalquila, (C3-C14) heteroarila, (C3-C14)aril-(C1-C6)alquileno-, -C(O) (C3-C14)aril-(C1-C6) alquileno-, -C(O)(C3-Ci4)arila, (C3-C6)cicloalquil-(Ci-C6)alquileno-, (C3-C14) heteroaril-(C1-C6)alquileno-, e (C3-C14)heterociclo-(C1- C6)alquileno-; em que qualquer alquila, alquileno, arila, heteroarila, cicloalquila, ou hetero-cicloalquila é opcionalmente substituído com um ou mais membros selecionados de halogênio, oxo, -COOH, -CN, -NO2, -OH, -NRdRe, -NRgS(O)2Rh, (Ci-C6)alcóxi, (Cs-Ci4)arila, (Ci-C6)halo- alquila e (C3-C14)arilóxi; em que Rd, Re, Rg, e Rh são cada qual independentemente selecionado de H, (C1-C6)alquila linear ou ramificada, (C3-C14)aril(C1- C6)alquileno- opcionalmente substituído, (C3-C14)arila, (C1- C6)hidro- xialquila opcionalmente substituída, (C1-C6)aminoalquila, H2N(CI-C6) alquileno-, (C3-C6)cicloalquila opcionalmente substituída, (C3-Ci4)hete- ro-cicloalquila opcionalmente substituída (C3-Ci4)heteroarila, opcionalmente substituída, (C3-C14)aril-(C1-C6)alquileno- opcionalmente substituído, NR'R"C(O)-, e (C3-C6)aril-(C3-C14)- cicloalquileno-.[000110] For example, US Patent Application Publication No. 2012/0129806 describes the arginase inhibitor of formula J:

Formula J; wherein: R2 is selected from H, (C1-C6) linear or branched alkyl, and (C1-Cβ)alkyl-C(O)-; W, X, Y, and Z are each independently selected from -C(R')(R'")-, -C(R"')2-, -CR"'-, -NR'"-, - N-, -O-, -C(O)-, and -S-, wherein no more than three of W, X, Y, and Z simultaneously represent a bond; at least one of W, X, Y, or Z is selected from -NR'"-, -N-, -O-, and -S-; and no more than two adjacent members of W, X, Y, and Z are simultaneously -O-, -S-, -N-, or -NR'"-; 1, m, n and p are each independently 0 or 1 or 2;

optionally represents one or more double bonds; D is selected from linear or branched (C3-C5)alkylene; R', R" and R'" are each independently selected from H, OH, S(O)Rd, S(O)2Rd, (C1-Cs)alkyl, (C3-C6)aryl, -NH2, -NH (C1-C6)alkyl, -N[(C1-C6)alkyl]2, -C(O)NRdRe, -C(O)(C1-C6)alkyl, -C(O)(C3-C14)aryl, -C(O)O(C1-C6)alkyl, -C(O)O(C3-C14)aryl, (C3-C6)cycloalkyl, (C3-C14)heterocycloalkyl, -C(O)(C3- C14)hetero-cycloalkyl, (C3-C14)heteroaryl, (C3-C14)aryl-(C1-C6)alkylene-, -C(O)(C3-C14)aryl-(C1-C6)alkylene-, -C (O)(C3-C14)aryl, (C3-C6)cycloalkyl-(C1-C6)alkylene-, (C3-C14)heteroaryl-(C1-C6)alkylene-, and (C3-C14)heterocycle-(C1) -C6)alkylene-; wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or hetero-cycloalkyl is optionally substituted with one or more members selected from halogen, oxo, -COOH, -CN, -NO2, -OH, -NRdRe, -NRgS(O )2Rh, (C1-C6)alkoxy, (Cs-C14)aryl, (C1-C6)haloalkyl and (C3-C14)aryloxy; wherein Rd, Re, Rg, and Rh are each independently selected from H, (C1-C6)linear or branched alkyl, (C3-C14)aryl(C1-C6)alkylene- optionally substituted, (C3-C14)aryl , optionally substituted (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, H2N(C1-C6)alkylene-, optionally substituted (C3-C6)cycloalkyl, optionally substituted (C3-C14)hetero-cycloalkyl ( C3-C14)heteroaryl, optionally substituted, (C3-C14)aryl-(C1-C6)alkylene-, NR'R"C(O)-, and (C3-C6)aryl-(C3-C14)- cycloalkylene-.

em que R5 é H ou alquila inferior, e as variáveis restantes são como definido para Fórmula J.[000111] When treated with anhydrous alcohol, the compound of formula J can be cyclized to form the compound of formula B: /OR5 B

where R5 is H or lower alkyl, and the remaining variables are as defined for Formula J.

[000112] In certain embodiments of the compound of formula B, R5 is lower alkyl, preferably methyl, ethyl, propyl, or isopropyl. more preferably, R5 is ethyl.

[000113] In certain embodiments, D is propylene.

[000114] In certain embodiments, a compound of the present invention may have a prodrug modification, for example, at the R1 position. For example, compounds of Formula I can have R1 equal to an amino acid side chain of an amino acid such as Arg or Lys. In certain such embodiments, the guanidino or amino group of such a side chain may be protected as, for example, an amide. Alternatively, in embodiments where R1 is a side chain of a serine residue, a hydroxyl group on the parent compound can be presented as an ester or a carbonate. In still other embodiments, where R1 is a side chain of a glutamic acid residue, a carboxylic acid group present in the parent compound can be presented as an ester. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the amide is hydrolyzed to the corresponding amino or guanidino group, the ester or carbonate is hydrolyzed to the hydroxyl, or the ester is hydrolyzed to the carboxylic acid).

[000115] In certain embodiments, the compounds of the description may be racemic. In certain embodiments, the compounds of the description can be enriched in one enantiomer. For example, a compound of the description may have more than 30% enantiomeric excess, 40% enantiomeric excess, 50% enantiomeric excess, 60% enantiomeric excess, 70% enantiomeric excess, 80% enantiomeric excess, 90% enantiomeric excess, or 95% enantiomeric excess or more.

[000116] The compounds of the description have more than one stereocenter. Consequently, the compounds of the description can be enriched in one or more diastereomers. For example, a compound of the description may be greater than 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 95% or greater. In certain embodiments, compounds of the disclosure have substantially one isomeric configuration at one or more stereogenic centers, and have multiple isomeric configurations at the remainder of the stereogenic centers.

[000117] In certain embodiments, the enantiomeric excess of the stereocenter carrying R1 is at least 40% enantiomeric excess, 50% enantiomeric excess, 60% enantiomeric excess, 70% enantiomeric excess, 80% enantiomeric excess, 90% enantiomeric excess, 92% enantiomeric excess, 94% enantiomeric excess, 95% enantiomeric excess, 96% enantiomeric excess, 98% enantiomeric excess or more.

[000118] As used herein, single bonds drawn without stereochemistry do not indicate the stereochemistry of the compound. The compound of formula (I) refers to an example of a compound for which no stereochemistry is indicated.

as ligações não cunha, em negrito indicam que o grupo -CO2Ra e o grupo (CH2)3B(ORc)2 são configurados estar cis um para o outro, porém as ligações não cunha em negrito representam a configuração absoluta (isto é, R ou S) do composto.[000119] As used herein, dashed or bold non-wedge bonds indicate relative but not absolute stereochemical configuration (eg, do not distinguish between the enantiomers of a given diastereomer). For example, in formula (Ia),

Non-wedge bonds in bold indicate that the -CO2Ra group and (CH2)3B(ORc)2 group are configured to be cis to each other, but non-wedge bonds in bold represent the absolute configuration (i.e., R or S) of the compound.

a ligação cunha em negrito indica a configuração absoluta do estereocentro ao qual ela é ligada, enquanto as ligações não cunha em negrito indicam que o grupo -CO2Ra e o grupo (CH2)3B(ORc)2 são configurados para estar cis um para o outro, porém não indicam a configuração absoluta de daqueles estereocentros. Portanto, o composto de fórmula (Ic) representa dois isômeros no total:

[000120] As used herein, dashed or bold wedge bonds indicate absolute stereochemical configuration. For example, in formula (Ic),

the wedge bond in bold indicates the absolute configuration of the stereocenter to which it is attached, while the non-wedge bonds in bold indicate that the -CO2Ra group and the (CH2)3B(ORc)2 group are configured to be cis to each other , but do not indicate the absolute configuration of those stereocenters. Therefore, the compound of formula (Ic) represents two isomers in total:

[000121] In certain embodiments, a therapeutic preparation of the compound of the description can be enriched to provide predominantly one enantiomer of a compound. An enantiomerically enriched mixture may comprise, for example, at least 60 mole percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mole percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question comprises less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1% compared to the amount of the other enantiomer, for example, in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it will be said to contain 98 mole percent of the first enantiomer and only 2% of the second enantiomer.

[000122] In certain embodiments, a therapeutic preparation can be enriched to predominantly provide a diastereomer of the compound of the description. A diastereomerically enriched mixture may comprise, for example, at least 60 mole percent of a diastereomer, or more preferably at least 75, 90, 95, or even 99 mole percent.

[000123] In certain embodiments, a preparation of the compound of the description may comprise at least 50% by mol, at least 60% by mol, at least 70% by mol, at least 80% by mol, at least 90% by mol, or at least 95 mol % of the cyclic alkoxy compounds of the description. In certain such embodiments, the balance of the preparation is the non-cyclized boronic ester counterpart or the cyclized but non-esterified boronic acid (eg, Formula I, R4 = H; Scheme 1).

[000124] In certain embodiments, the compounds of the disclosure exhibit an improved pharmacokinetic profile relative to existing arginase inhibitors. In one embodiment, the cyclic alkoxylated compounds of the invention, when administered to a subject or subjects, provide an increased (or decreased) Tmax relative to that obtained by administering a non-cyclized boronic ester counterpart, as referred to herein, from at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, and under similar conditions and administered at similar dosages. In one embodiment, the cyclic alkoxylated compounds of the invention, when administered to an individual or multiple individuals, provide an increased (or decreased) C max relative to that obtained by administering an uncyclized free boronic ester counterpart, as referred to herein, from at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, and under similar conditions and administered at similar dosages.

[000125] In certain embodiments, the compounds of the disclosure exhibit improved bioavailability over existing arginase inhibitors. In one embodiment, the cyclic alkoxylated compounds of the invention, when administered to a subject or subjects, provide increased bioavailability over that obtained by administering an uncyclized free boronic ester counterpart (e.g., compounds of Formula J described herein). of at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 45% at least about 50%, or at least about 55%, or at least about 60%, such as at least 65%, the bioavailability being determined as AUC(0-infinity) and under similar conditions and administered at similar dosages.

[000126] Cyclic alkoxylated compounds of the invention are typically less hygroscopic than free boronic ester counterparts (eg, compounds of Formula J described herein). For example, compound 10e, depicted in the examples, has low water content and is resistant to water absorbance up to about 60% relative humidity, while its free boronic acid counterpart, compound 10, has higher water content and absorbs increasing amounts of water as humidity increases, resulting in a much less defined composition.

[000127] The cyclic alkoxylated compounds of the invention can be about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% less hygroscopic than their counterparts of free boronic ester as assessed by standard techniques such as thermogravimetric analysis (TGA) or dynamic vapor sorption (DVS). These values can be used to define a range, such as from about 40% to about 20%.

[000128] In certain embodiments, the cyclic alkoxylated compounds of the invention are crystalline. Cyclic alkoxylated compounds of the invention typically have higher degrees of crystallinity than their free boronic ester counterparts (eg, compounds of Formula J described herein). For example, compound 10e also shows peaks defined by X-ray powder diffraction that are not shown with respect to its free boronic acid counterpart, compound 10, which is amorphous.

[000129] In certain embodiments, the cyclic alkoxylated compounds of the invention have a purity level of greater than 96%, 97%, or 98%. In certain embodiments, the cyclic alkoxylated compounds of the invention have a purity level of greater than 99%. In certain embodiments, the cyclic alkoxylated compounds of the invention have a purity level of greater than 99.5%. In certain embodiments, the cyclic alkoxylated compounds of the invention have a purity level of greater than 99.8%.

[000130] As a result, the cyclic alkoxylated compounds of the invention may have advantageous properties, allowing the preparation of more stable compositions, exhibiting better handling properties in the manufacturing process, and ultimately may result in compositions having greater purity and stability. In some embodiments, a pharmaceutical composition comprising a cyclic alkoxylated compound of the invention, when exposed to an environment of at least 50% humidity for at least 24 hours, captures less than 50% (preferably less than 25%, or even less than 10% or 5%) of the water that a corresponding composition of a free uncyclized boronic ester counterpart of the compound takes up under identical conditions.

[000131] In certain embodiments, the cyclic alkoxylated compounds of the present invention exhibit improved stability, such as increased storage stability, with respect to structurally related compounds that have a free, non-cyclized boronic acid group (for example, compounds of Formula J described on here). For example, the present compounds or pharmaceutical compositions can exhibit improved storage stability by exhibiting less than about 10%, 7%, 5%, 4%, 3%, 2%, 1%, or 0.5% impurities. by weight following storage under stressed conditions. Stressed conditions include storage for at least one, two, three, four, five or six months at 25°C and 60% RH, at 30°C and 65% RH, or at 40°C and 75% RH. Such compounds or compositions can be considered to be storage stable. In some embodiments, the impurities are associated with decomposition or degradation of the subject compound. Determining the amount of impurities present in a sample of the present compounds or pharmaceutical compositions that has been subjected to the stressed conditions can be performed by typical analytical methods known in the art, such as by HPLC or NMR analysis.

[000132] In certain embodiments, the present compounds or pharmaceutical compositions, exhibit improved storage stability by exhibiting little or no change in the purity profile after being subjected to the stressed conditions as defined herein. For example, following being subjected to the stressed conditions, the cyclic alkoxylated compounds of the invention or pharmaceutical compositions comprising the cyclic alkoxylated compounds of the invention may exhibit a decrease in purity of about 10, 7, 5, 4, 3, 2, 1, or 0.5 percentage points or less (eg, a decrease from 98% purity to 97% purity would be a decrease of 1 percentage point or less).

Treatment Methods

[000133] Several specific methods for T cell activation have recently shown considerable promise in the treatment of tumors. One such method involves activating T cells by blocking the CTLA-4 T cell surface antigen by the ipilimumab antibody. A second method is to prevent activation of immune checkpoints by blocking the interaction of programmed cell death protein 1, or PD-1, expressed in T cells and its ligand, PD-L1 found in many tumors. A third method is to activate the T cell receptor by supplying important stimulating factors or nutrients such as tryptophan.

[000134] Inhibitors of indoleamine dioxygenase, or IDO, have been shown to restore extracellular tryptophan without which the T cell receptor cannot become active.

[000135] Arginine, like tryptophan, is an amino acid that is essential for the function of cytotoxic T cells. Without arginine, tumor-specific cytotoxic T cells fail to express a functional T cell receptor on their surface and as a result are unable to activate, proliferate, or mount an effective antitumor response. In response to tumor-secreted factors, myeloid-derived suppressor cells, or MDSCs, accumulate around the tumor and secrete the enzyme arginase, resulting in arginine depletion of the tumor microenvironment.

[000136] Arginine depletion due to elevated levels of arginase has been observed in renal cell carcinoma and acute myeloid leukemia. In addition, significant MDSC infiltrates have been observed in pancreatic, breast, and other types of tumors. Certain embodiments of the present invention provide a method of treating cancer by increasing arginine levels in a tumor microenvironment, thereby allowing activation of the body's cytotoxic T cells.

[000137] One way to increase arginine levels in the tumor microenvironment is to inhibit arginase. Arginase inhibitors, such as the compounds of the disclosure, can promote an anti-tumor immune response by restoring arginine levels, thereby allowing activation of the body's cytotoxic T cells.

[000138] Accordingly, in certain embodiments, the description relates to methods for treating or preventing cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) (which includes compounds of formulas (I'), (I''), (I"'), (I*), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih)), or a pharmaceutical composition comprising said compound.

[000139] In certain embodiments, the cancer that is treated by the methods of the invention is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Cell Carcinoma Basal Cancer, Biliary Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal Cord Tumor, Brain Stem Glioma, Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System, Embryonic Tumors of the Central Nervous System, Breast Cancer , Bronchial Tumors, Burkitt's Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary Site, Central Nervous System Cancer, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Cancer Colon Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ (DCIS), Embryonic Tumors, Endometrial Cancer, Ependymobl Astoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing's Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Cellular Cancer, Fibrous Histiocytoma of Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Ovarian Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Hair Cell Leukemia, Head and Neck Cancer , Heart Cancer, Hepatocellular Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin's Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Kaposi's Sarcoma, Kidney Cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Cancer of the Oral Cavity and Lips, Liver Cancer, Lobular Carcinoma In Situ (LCIS), Lung Cancer, Lymphoma, Li AIDS-related lymphoma, Macroglobulinemia, Male Breast Cancer, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Malignant Mesothelioma, Metastatic Squamous Neck Cancer with Primary Cult, Intermediate Tract Carcinoma Involving the NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndrome, Plasma Cell Neoplasm/Multiple Myeloma, Mycoses Fungoides, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma, Myeloproliferative Disorder, Cavity Cancer Nasal, Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin's Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Mouth Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Cancer of the Paranasal Sinuses, Cancer of the Nasal Cavity, Cancer of the Parathyroid, Cancer of the Penis o, Pharyngeal Cancer, Pheochromocytoma, Intermediate Differentiation Pineal Parenchymal Tumors, Pineoblastoma, Pituitary Tumor, Plasma Cell Neoplasm, Pleuropulmonary Blastoma, Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Cancer Cancer of the Renal Pelvis, Cancer of the Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Cancer of the Salivary Gland, Sarcoma, Sézary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue, Squamous Cell Carcinoma, Squamous Neck Cancer with Cultivated Primary Site, Stomach Cancer, Supratentorial Primate Neuroectodermal Tumors, T-Cell Lymphoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Gestational Trophoblastic Tumor, Primary Unknown, Unusual Childhood Cancer, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Waldens Macroglobulinemia trom, or Wilms Tumor.

[000140] In certain embodiments, the cancer that is treated by the methods of the invention is a variety of acute myeloid leukemia (AML), breast cancer, colorectal cancer, chronic myelogenous leukemia (CML), esophageal cancer, gastric cancer, lung cancer, melanoma, non-small cell lung cancer (NSCLC), pancreatic cancer, prostate cancer, or kidney cancer.

[000141] In certain embodiments, the cancer is selected from blacancer of the bladder, breast cancer (including TNBC), cervical cancer, colorectal cancer, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), esophageal adenocarcinoma, glioblastoma, head and neck cancer, leukemia (acute and chronic), low-grade glioma, lung cancer (including adenocarcinoma, non-small cell lung cancer, and squamous cell carcinoma), Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL) , melanoma, multiple myeloma (MM), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer (including renal clear cell carcinoma and renal papillary cell carcinoma), and stomach cancer.

[000142] Combination therapy is an important treatment modality in many disease contexts, such as cancer. Recent scientific advances have increased understanding of the pathophysiological processes underlying these other complex diseases. This increased understanding has provided an impetus to develop new therapeutic methods using combinations of drugs that target multiple therapeutic targets to improve treatment response, minimize the development of resistance, or minimize adverse events. In contexts where combination therapy provides significant therapeutic advantages, there is growing interest in developing combinations with new investigational drugs, arginase inhibitors such as arginase.

[000143] When considering the administration of multiple therapeutic agents together, one must be concerned with what type of drug interactions will be observed. This action can be positive (when the effect of the drug is increased) or antagonistic (when the effect of the drug is decreased) or a new side effect can be produced that it does not produce by itself.

[000144] When the interaction causes an increase in the effects of one or both of the drugs in the interaction, the degree to which the effect of the drugs combined is greater than that of administering either drug alone can be calculated resulting in what is called the "combination index " (CI) (Chou and Talalay, 1984). A blending index at or around 1 is considered "additive"; while a value greater than 1 is considered "synergistic".

[000145] The present invention relates to methods for combination therapy in the treatment or prevention of cancer comprising an arginase inhibitor (for example, a compound of the description) and one or more additional chemotherapeutic agents.

[000146] Certain embodiments of the description relate to the treatment of cancer comprising jointly administering a chemotherapeutic agent and a compound of the description.

[000147] In certain embodiments, the chemotherapeutic is an immunostimulatory agent. For example, the immunostimulating agent can be a pro-inflammatory agent.

[000148] The chemotherapeutic agent that can be administered together with the arginase inhibitors described herein in the methods of the invention include ABT-263, afatinib dimaleate, aminoglutethimide, ansacrine, anastrozole, asparaginase, axitinib, Bacillus Calmette-Guérin vaccine (bcg) , bevacizumab, BEZ235, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine , dacarbazine, dactinomycin, daunorubicin, demethoxyviridine, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluosteroneuracil and 5-fluorouracil , flutamide, gefitinib, gemcitabine, genistein, goser elina, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine MK2206, mitomycin, mitotane, mitoxantrone, mutamycin, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, ramuciberum, romidepsin, rucaparib, selumetinib, sirolimus, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA).

[000149] In certain embodiments, the chemotherapeutic agent that can be administered with the arginase inhibitors described herein in the methods of the invention include abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab, mafenatox, apolizumab, atezolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab , epacadostat, epratuzumab, indoximod, inotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MGA012, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, timalilizumab, or tremolizumab.

[000150] In certain embodiments, the chemotherapeutic agent is ipilimumab, MGA012, nivolumab, pembrolizumab, or pidilizumab.

"8 in 1" Metilprednisolona, Vinacristina, Lomustina, Procarbazina, Hidroxiureia, Cisplatina, Citarabina, Dacarbazina[000151] Many combination therapies have been developed for the treatment of cancer. In certain embodiments, the compounds of the description can be conjointly administered with a combination therapy. Examples of the combination therapies with which the compounds of the disclosure can be conjointly administered are included in Table 1. Table 1: Exemplary combination therapies for the treatment of cancer.

"8 in 1" Methylprednisolone, Vinacrystine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin, Cytarabine, Dacarbazine

[000152] In certain embodiments, the co-administered chemotherapeutic agent is selected from a metabolic enzyme inhibitor, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase 1 or 2, pyruvate dehydrogenase kinase, fatty acid synthase, and glutaminase. In some embodiments, the inhibitor inhibits lactate dehydrogenase 1 or 2, or glutaminase. In certain embodiments, the inhibitor is CB-839.

[000153] In some embodiments, the conjointly administered chemotherapeutic agent is an immuno-oncology therapeutic agent, such as an inhibitor of CTLA-4, indoleamine 2,3-dioxygenase, and/or PD-1/PD-L1. In certain embodiments, the immuno-oncology therapeutic agent is abeagovomab, adecatumumab, afutuzumab, anatumomab, mafenatox, apolizumab, atezolizumab, belinatumomab, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, nivolumab, lamberolizumab ocaratuzumab, olatatumab, pemberolizumab, pidilizumab, ticilimumab, samalizumab, or tremelimumab. In some embodiments, the immuno-oncology agent is indoximod, ipilimumab, nivolumab, pembrolizumab, or pidilizumab. In certain embodiments, the immuno-oncology therapeutic agent is ipilimumab.

[000154] Exemplary immuno-oncology agents are described in Adams, J. L. et al. "Big Opportunities for Small Molecules in Immuno-Oncology" Nature Reviews Drug Discovery 2015, 14, pages 603-621, the contents of which are hereby incorporated by reference.

[000155] In certain embodiments, the co-administered chemotherapeutic agent is a pro-inflammatory agent. In certain embodiments, the pro-inflammatory agent administered with the arginase inhibitors of the invention is a cytokine or a chemokine.

[000156] Pro-inflammatory cytokines are predominantly produced by activated macrophages and are involved in the down-regulation of inflammatory reactions. Exemplary proinflammatory cytokines include, but are not limited to, IL-1, IL-1β, IL-6, IL-8, TNF-α, and IFN-γ.

[000157] Chemokines are a group of small cytokines. Pro-inflammatory chemokines promote recruitment and activation of multiple leukocyte lineages (eg, lymphocytes, macrophages). Chemokines are related in primary structure and share several conserved amino acid residues. In particular, chemokines typically include two or four cysteine residues that contribute to three-dimensional structure via the formation of disulfide bonds. Chemokines can be classified into one of four groups: C-C chemokines, C-X-C chemokines, C chemokines, and C-X3-C chemokines. C-X-C chemokines include various chemoattractants and neutrophil activators, such as interleukin 8 (IL-8), PF4, and neutrophil activating peptide 2 (NAP-2). C-C chemokines include, for example, RANTES (Regulated on Activation, Expressed in Normal T, and Secreted), macrophage inflammatory proteins 1-alpha and 1-beta (MIP-1α and MIP-1β), eotaxin, and human monocyte chemotactic proteins 1 to 3 (MCP-1, MCP-2, MCP-3), which were characterized as chemoattractants and activators of monocytes or lymphocytes. Accordingly, exemplary pro-inflammatory chemokines include MIP-1α, MIP-1β, MIP-1Y, MCP-1, MCP-2, MCP-3, IL-8, PF4, NAP-2, RANTES, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL2, CXCL8, and CXCL10.

[000158] In certain embodiments, the method of treating or preventing cancer also comprises administering one or more non-chemical methods of treating cancer, such as radiation therapy, surgery, thermoablation, focused ultrasound therapy, cryotherapy, or a combination of the foregoing.

[000159] Cellular roads operate more like networks than superhighways. There are multiple redundancies or alternate routines, which are activated in response to inhibition of a pathway. This redundancy promotes the emergence of resistant cells or organisms under the selective pressure of a targeted agent, resulting in drug resistance and clinical relapse.

[000160] In certain embodiments of the description, the chemotherapeutic agent is administered simultaneously with the arginase inhibitor. In certain embodiments, the chemotherapeutic agent is administered within a period of from about 5 minutes to about 168 hours before or after the arginase inhibitor.

[000161] The present invention relates to combination therapies comprising an immuno-oncology agent selected from CTLA-4, indoleamine 2,3-dioxygenase, and PD-1/PD-L1 inhibitors, and an arginase inhibitor of formula (I). In certain embodiments, combination therapy treats or prevents cancer, an immune disorder, or a chronic infection.

[000162] The present invention relates to combination therapies comprising an immuno-oncology agent selected from inhibitors of an indoleamine 2,3-dioxygenase, and PD-1/PD-L1, and an arginase inhibitor of formula (I ), such as combinations with epacadostate and nivolumab, epacadostate and pembrolizumab, and epacadostate and MGA012. In certain embodiments, combination therapy treats or prevents cancer, an immune disorder, or a chronic infection.

[000163] In certain embodiments, the description refers to methods for treating or preventing an immunological disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the description (for example, a compound of formula (I), or a pharmaceutical composition comprising said compound.

[000164] In certain embodiments, the immune disease is selected from ankylosing spondylitis, Crohn's disease, erythema nodosum leprosum (ENL), graft versus host disease (GVHD), HIV-associated wasting syndrome, lupus erythematosus, kidney transplant rejection organ, post-polycythemia, psoriasis, psoriatic arthritis, recurrent aphthous ulcers, rheumatoid arthritis (RA), severe recurrent aphthous stomatitis, systemic sclerosis and tuberous sclerosis.

[000165] In certain embodiments, the method for treating or preventing an immune disease also comprises conjointly administering an immuno-oncology therapeutic agent, as described above.

[000166] In certain embodiments, the description refers to methods for treating or preventing a chronic infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the description (for example, a compound of formula ( I)), or a pharmaceutical composition comprising said compound.

[000167] In certain embodiments, the chronic infection is selected from bladder infection, chronic fatigue syndrome, cytomegalovirus/epstein barr virus, fibromyalgia, hepatitis B virus (HBV), hepatitis C virus (HCV), HIV virus/ AIDS, mycoplasma infection and urinary tract infections.

[000168] In certain embodiments, the method for treating or preventing a chronic infection also comprises conjointly administering an immuno-oncology therapeutic agent, as described above.

[000169] In certain embodiments, the description refers to a method for treating or preventing a disease or condition associated with expression or activity of arginase I, arginase II, or a combination thereof in an individual, comprising administering to the individual a therapeutically effective amount of at least one of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof.

[000170] In certain embodiments, the disease or condition is selected from cardiovascular disorders, sexual disorders, wound healing disorders, gastrointestinal disorders, autoimmune disorders, immune disorders, infections, lung disorders, and hemolytic disorders.

[000171] In certain embodiments, the disease or condition is a cardiovascular disorder selected from systemic arterial hypertension, pulmonary arterial hypertension (PAH), high-altitude pulmonary arterial hypertension, ischemic reperfusion injury (IR), myocardial infarction, and atherosclerosis.

[000172] In certain embodiments, the disease or condition is pulmonary arterial hypertension (PAH).

[000173] In certain embodiments, the disease or condition is myocardial infarction or atherosclerosis.

[000174] In certain embodiments, the disease or condition is a lung disorder selected from chemically induced pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD) and asthma.

[000175] In certain embodiments, the disease or condition is an autoimmune disorder selected from encephalomyelitis, multiple sclerosis, antiphospholipid 1 syndrome, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyradiculoneuropathy, dermatitis herpetiformis, dermatomyositis, myasthenia gravis, pemphigus, rheumatoid arthritis, rigid person, type 1 diabetes, ankylosing spondylitis, paroxysmal nocturnal hemoglobinuria (PNH), paroxysmal cold hemoglobinuria, severe idiopathic autoimmune hemolytic anemia, and Goodpasture's syndrome.

[000176] In certain embodiments, the disease or condition is a myeloid-derived suppressor cell mediated T cell dysfunction (MDSC), human immunodeficiency virus (HIV), autoimmune encephalomyelitis, and ABO incompatibility transfusion reaction.

[000177] In certain embodiments, the disease or condition is a myeloid-derived suppressor cell (MDSC) mediated T cell dysfunction.

[000178] In certain embodiments, the disease or condition is a hemolytic disorder selected from sickle cell disease, thalassemias, hereditary spherocytosis, stomatocytosis, pyruvate kinase deficiency from microangiopathic hemolytic anemias, infection-induced anemia, cardiopulmonary bypass, and heart valve-induced mechanical anemia and chemically induced anemia.

[000179] In certain embodiments, the disease or condition is gastrointestinal disorder selected from gastrointestinal motility disorders, gastric cancer, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and gastric ulcer.

[000180] In certain embodiments, the disease or condition is a sexual disorder selected from Peyronie's disease and erectile dysfunction.

[000181] In certain embodiments, the disease or condition is ischemia-reperfusion (IR) injury selected from liver IR, kidney IR, and myocardial IR.

[000182] In certain embodiments, the disease or condition is selected from inflammation of kidney disease, psoriasis, leishmaniasis, neurodegenerative diseases, wound healing, human immunodeficiency virus (HIV), hepatitis B virus (HBV), H. pylori, fibrotic disorders, arthritis, candidiasis, periodontal disease, keloids, adenotonsillar disease, African sleeping sickness, and Chagase disease.

[000183] In certain embodiments, the disease or condition is a wound healing disorder selected from infected and non-infected wound healing.

[000184] In certain embodiments, a combination therapy regimen is more effective than an arginase inhibitor therapy regimen as a single agent, or a therapeutic regimen of the additional chemotherapeutic agent as a single agent.

Combinations of Arginase Inhibitors of the Invention with IDO Inhibitors

[000185] The invention relates to methods for treating or preventing cancer in an individual, comprising jointly administering to an individual in need thereof an arginase inhibitor of formula (I) (which includes compounds of formulas (I'), (I''), (I"'), (I*), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and a IDO inhibitor The IDO inhibitor can be a compound described in, or a compound having a structure of any of the formulas described herein In certain embodiments, the methods also comprise co-administering one or more additional chemotherapeutic agents.

[000186] In certain embodiments, the subject is a human.

[000187] The invention also relates to pharmaceutical kits, comprising an IDO inhibitor, an arginase inhibitor of formula (I), and optionally instructions on how to administer the IDO inhibitor and the arginase inhibitor.

[000188] In certain embodiments, the IDO inhibitor is epacadostat, norarman, rosmarinic acid, 1-methyltryptophan, a tryptophan derivative, indoximod, or NLG919, or pharmaceutically acceptable salts thereof. In certain embodiments, the IDO inhibitor is epacadostat. In certain embodiments, the IDO inhibitor has a structure of any of the formulas described herein. In certain embodiments, the IDO inhibitor is a compound of any of the formulas described herein.

[000189] IDO inhibitors appropriate for use in compositions and methods described here are described in the US patent request publications No. 20160158353, US2015353546, US2015 291632, US2015291557, US2015246898, US2016 002242, US201650, 20150 ; U.S. Patent Nos. 8748461, 9309273, 8809378, 8883797, 8669274, 8389543, 9447073, 9150527, 9056855, 8987315, 9409914, 9120804, 9073944, 9320735, 5; PCT Application Publications Nos. WO2016 059412, WO2016051181, WO2016057986, WO2016196890; and European Patent Publications Nos EP2804858, EP2563771; which are hereby incorporated by reference in their entirety, and in particular for the composite structures described herein.

[000190] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 7767675, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:

[000191] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas or a pharmaceutically acceptable salt thereof:

[000192] The variable definitions, modalities and structures of compounds are as described in US Patent number 7767675.

Fórmula (III).[000193] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 8088803, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

Formula (III).

[000194] In some embodiments, the IDO inhibitor is a compound selected from Formula F15, F19, and F28, or a pharmaceutically acceptable salt thereof:

[000195] The variable definitions, modalities and structures of compounds are as described in US Patent number 8088803.

[000196] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 8,377,976, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof:

[000197] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000198] The variable definitions, modalities and structures of compounds are as described in US Patent number 8377976.

[000199] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 8507541, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (V), or a pharmaceutically acceptable salt thereof: Formula (V).

Fórmula (Vd).[000200] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

Formula (Vd).

[000201] The variable definitions, modalities and structures of compounds are as described in US Patent number 8507541.

[000202] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 9,321,755, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (VI), or a pharmaceutically acceptable salt thereof: Formula (VI).

[000203] In some embodiments, the IDO inhibitor is a compound selected from Formula F5, F8, F10, F15, F16, F17, F18, F19, and F20, or a pharmaceutically acceptable salt thereof:

[000204] The variable definitions, modalities and structures of compounds are as described in US Patent number 9321755.

[000205] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 8748469, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (VII), Formula (VIII), or a pharmaceutically acceptable salt thereof: Formula (VII); or Formula (VIII).

[000206] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000207] The variable definitions, modalities and structures of compounds are as described in US Patent number 8748469.

[000208] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 9260434, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (X), or a pharmaceutically acceptable salt thereof: Formula (X).

[000209] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000210] The variable definitions, modalities and structures of compounds are as described in US Patent number 9260434.

[000211] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent number 9120804, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof:

[000212] The variable definitions, modalities and structures of compounds are as described in US Patent number 9120804.

[000213] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2008/0146624, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XII), (XIII), or a pharmaceutically acceptable salt thereof: Formula (XIII).

[000214] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof: Formula (XIVr).

[000215] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2008/0146624.

[000216] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2008/0182882, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XV), or a pharmaceutically acceptable salt thereof:

[000217] In some embodiments, the IDO inhibitor is a compound of Formula (XVa), Formula (XVb), or a pharmaceutically acceptable salt thereof:

[000218] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2008/0182882.

[000219] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2007/0203140, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof: Formula (XVI).

[000220] Variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2007/0203140.

[000221] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2008/0119491. In some embodiments, the IDO inhibitor is a compound of Formula (XVII), or a pharmaceutically acceptable salt thereof:

[000222] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000223] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2008/0119491.

[000224] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0289238, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XVIII), or a pharmaceutically acceptable salt thereof:

[000225] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000226] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0289238.

K Fórmula (XIX).[000227] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0229843, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XIX), or a pharmaceutically acceptable salt thereof:

K Formula (XIX).

[000228] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000229] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0229843.

.[000230] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0046596, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XX), or a pharmaceutically acceptable salt thereof: Formula (XX)

.

[000231] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000232] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0046596.

[000233] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2011/0053941 or 2013/0289083, which are hereby incorporated by references herein at its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXI), Formula (XXII), or a pharmaceutically acceptable salt thereof:

[000234] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000235] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2011/0053941 or 2013/0289083.

[000236] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0060266, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXIX), or a pharmaceutically acceptable salt thereof: Formula (XXIX).

[000237] In some embodiments, the IDO inhibitor is a compound selected from the following formulas, or a pharmaceutically acceptable salt thereof:

[000238] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0060266.

[000239] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/075711, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXX), or a pharmaceutically acceptable salt thereof: Formula (XXX).

[000240] In some embodiments, the IDO inhibitor is a compound selected from a compound of the following formulas, or a pharmaceutically acceptable salt thereof:

[000241] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/075711.

em sua totalidade. Em algumas modalidades, o inibidor de IDO é um composto de Fórmula (XXXI), um composto de Fórmula (XXXII), ou um sal farmaceuticamente aceitável do mesmo:

[000242] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0022619, which is hereby incorporated by reference herein

in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXXI), a compound of Formula (XXXII), or a pharmaceutically acceptable salt thereof:

[000243] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0022619.

Fórmula (XXXIV).[000244] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0060237, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXXIII), a compound of Formula (XXXIV), or a pharmaceutically acceptable salt thereof:

Formula (XXXIV).

[000245] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0060237.

Fórmula (XXXVI).[000246] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0137595, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXXV), a compound of Formula (XXXVI), or a pharmaceutically acceptable salt thereof:

Formula (XXXVI).

[000247] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0137595.

[000248] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0143870, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXXVII), a compound of Formula (XXXVIII), or a pharmaceutically acceptable salt thereof:

[000249] The variable definitions, modalities and structures of Americana number 2016/0143870.

[000250] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0200674, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XXXIX), a compound of Formula (XL), or a pharmaceutically acceptable salt thereof:

[000251] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0200674.

[000252] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0289171, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XLI), a compound of Formula (XLII), or a pharmaceutically acceptable salt thereof:

[000253] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0289171.

[000254] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0137652, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XLIII), or a pharmaceutically acceptable salt thereof:

[000255] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000256] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0137652.

[000257] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in US Patent Publication number 2016/0137653, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XLIV), or a pharmaceutically acceptable salt thereof:

Fórmula (XLIVn).[000258] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

Formula (XLIVn).

[000259] The variable definitions, modalities and structures of compounds are as described in US Patent Publication number 2016/0137653.

[000260] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2014 141110, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XLV), or a pharmaceutically acceptable salt thereof:

[000261] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof: Formula (XLVa)

[000262] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2014141110.

[000263] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2016027241, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XLVI), or a pharmaceutically acceptable salt thereof: Formula (XLVI).

[000264] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000265] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2016027241.

[000266] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2016 181348, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XLVII), or a pharmaceutically acceptable salt thereof: Formula (XLVII).

[000267] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000268] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2016181348.

[000269] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2016051181, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (XLIX), or a pharmaceutically acceptable salt thereof:

[000270] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000271] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2016051181.

[000272] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2016059412, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (L), or a pharmaceutically acceptable salt thereof:

[000273] In some embodiments, the IDO inhibitor is a compound selected from the following formulas, or a pharmaceutically acceptable salt thereof:

[000274] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2016059412.

[000275] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2015 119944, which corresponds to European Patent Publication number: EP3102237, which are hereby incorporated by reference herein in their entirety. In some embodiments, the IDO inhibitor is a compound of Formula (LI), or a pharmaceutically acceptable salt thereof:

[000276] In some embodiments, the IDO inhibitor is a compound selected from Formula (LII) and Formula (LIII), or a pharmaceutically acceptable salt thereof:

[000277] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2015119944.

[000278] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2016 073738, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (LIV), or a pharmaceutically acceptable salt thereof:

[000279] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000280] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2016073738.

[000281] In some embodiments, IDO inhibitors suitable for use in the compositions and methods described herein are the IDO inhibitors described in PCT Application Publication number WO2015 188085, which is hereby incorporated by reference herein in its entirety. In some embodiments, the IDO inhibitor is a compound of Formula (LV), or a pharmaceutically acceptable salt thereof:

[000282] In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000283] The variable definitions, modalities and structures of compounds are as described in PCT Application Publication number WO2015188085.

[000284] In particular embodiments, the description refers to methods of treating cancer by administering to a human subject epacadostate and an arginase inhibitor having one of the following formulas, or a pharmaceutically acceptable salt thereof:

[000285] In some such embodiments, epacdostat and an arginase inhibitor described in the schematic below are provided in a single composition. In another embodiment, epacdostat and an arginase inhibitor described in the schematic below are administered in separate pharmaceutical compositions.

Definitions

[000286] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[000287] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group and can be represented, for example, by the formula hydrocarbylC(O)NH-.

[000288] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[000289] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached to it. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[000290] The term "alkoxyalkyl" refers to an alkyl group substituted with alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[000291] The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond.

[000292] An "alkyl" or "alkane" group is a straight or branched chain non-aromatic hydrocarbon that is completely saturated. Typically, a straight or branched chain alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight or branched chain alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A straight or branched chain C1-C6 alkyl group is also referred to as a "lower alkyl" group.

[000293] The term "Cx-y" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups containing from x to y carbons in the chain. For example, the term "Cx-yalkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2, 2,2-trifluoroethyl, etc. C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms "C2-yalkenyl" and "C2-yalkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond, respectively.

[000294] The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group.

[000295] The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[000296] The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", the latter of which refers to refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may run on one or more carbons that are included or not included in one or more triple bonds. However, such substituents include all those contemplated for alkyl groups, as described above, except where stability is prohibitive. For example, replacement of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

em que cada R10 independentemente representa um hidrogênio ou grupo hidrocarbila, ou dois R10 são considerados juntamente com o átomo de N ao qual eles são ligados completar um heterociclo tendo de 4 a 8 átomos na estrutura de anel.[000297] The term "amide", as used herein, refers to a group

wherein each R10 independently represents a hydrogen or hydrocarbyl group, or two R10s are considered together with the N atom to which they are attached to complete a heterocycle having from 4 to 8 atoms in the ring structure.

em que cada R10 independentemente representa um hidrogênio ou um grupo hidrocarbila, ou dois R10 são considerados juntamente com o átomo de N ao qual eles são ligados completar um heterociclo tendo de 4 a 8 átomos na estrutura do anel.[000298] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and salts thereof, for example, a moiety that can be represented by

wherein each R10 independently represents a hydrogen or a hydrocarbyl group, or two R10s are considered together with the N atom to which they are attached to complete a heterocycle having from 4 to 8 atoms in the ring structure.

[000299] The term "aminoalkyl", as used herein, refers to an alkyl group substituted with an amino group.

[000300] The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group.

[000301] The term "aryl" as used herein includes substituted or unsubstituted single-ring aromatic groups in which each ring atom is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings, in which at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Accordingly, the term "aryl" can encompass (C5-C10) and (C6-C10) aryl groups. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

em que R9 e R10 independentemente representam hidrogênio ou um grupo hidrocarbila, tal como um grupo alquila, ou R9 e R10 considerados juntamente com o átomo(s) interveniente completar um heterociclo tendo de 4 a 8 átomos na estrutura do anel.[000302] The term "carbamate" is recognized in the art and refers to a group

wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R9 and R10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[000303] The terms "carbocycle", and "carbocyclic", as used herein, refer to a saturated or unsaturated ring, in which each ring atom is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. "Carbocycle" includes 6- to 7-membered monocyclic and 8- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules, in which one, two or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle, in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocycle can be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, when valence permits, is included in the definition of a carbocyclic. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0] hept-3-ene. "Carbocycles" can be substituted in any one or more positions capable of carrying a hydrogen atom.

[000304] A "cycloalkyl" group is a cyclic hydrocarbon that is completely saturated. "Cycloalkyl" includes both monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules, in which one, two or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[000305] The term "(cycloalkyl)alkyl", as used herein, refers to an alkyl group substituted with a cycloalkyl group.

[000306] The term "carbonate" is recognized in the art and refers to a group -OCO2-R10, where R10 represents a hydrocarbyl group.

[000307] The term "carboxy", as used herein, refers to a group represented by the formula -CO2H.

[000308] The term "ester", as used herein, refers to a group -C(O)OR10 where R10 represents a hydrocarbyl group.

[000309] The term "ether", as used herein, refers to a hydrocarbyl group bonded through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetric or non-symmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[000310] The terms "halo" and "halogen" as used herein mean halogen and include chlorine, fluorine, bromine, and iodine.

[000311] The term "heteroaralkyl", as used herein, refers to an alkyl group substituted with a heteroaryl group.

[000312] The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, where neither of the two heteroatoms are adjacent.

[000313] The term "heteroaryl" includes substituted or unsubstituted single aromatic ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" also include polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings, in which at least one of the rings is heteroaromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Accordingly, the term "heteroaryl" can encompass (C2-C10) and (C2-C10) heteroaryl groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[000314] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[000315] The terms "heterocycloalkyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "hetero-cycloalkyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings in which at least one of the rings is heterocyclic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl. Hetero-cycloalkyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactans, and the like.

[000316] The term "(heterocycloalkyl)alkyl", as used herein, refers to an alkyl group substituted with a heterocycloalkyl group.

[000317] The term "hydrocarbyl", as used herein, refers to a group that is bonded through a carbon atom that does not have a substituent of =O or =S, and typically has at least one carbon- hydrogen and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for purposes of this application, but substituents such as acetyl (which has an =O substituent on the linking carbon) and ethoxy (which is bonded through of oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[000318] The term "hydroxyalkyl", as used herein, refers to an alkyl group substituted with a hydroxy group.

[000319] The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or less. A "lower alkyl", for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they appear alone or in combination with other substituents, such as in the hydroxyalkyl and aralkyl recitations (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[000320] The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings (for example, cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls), in which two or more atoms are common to two adjacent rings, for example, the rings are "fused rings". Each of the polycycle rings can be replaced or not replaced. In certain embodiments, each polycycle contains from 3 to 10 ring atoms, preferably from 5 to 7.

[000321] The term "silyl" refers to a silicon moiety with three hydrocarbyl moieties attached to it.

[000322] The term "substituted" refers to moieties having substituents substituting a hydrogen on one or more carbons of the structure. It will be understood that "substitution" or "substituted with" includes the implied proviso that such substitution conforms to the allowable valency of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, that it does not undergo transformation spontaneously such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any substituent described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate , a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that the substituents themselves can be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include both substituted and unsubstituted variants.

[000323] The term "sulfate" is art-recognized and refers to the -OSO3H group, or a pharmaceutically acceptable salt thereof.

em que R9 e R10 independentemente representam hidrogênio ou hidrocarbila, tal como alquila, ou R9 e R10 considerados juntamente com o átomo(s) interveniente completar um heterociclo tendo de 4 a 8 átomos na estrutura do anel.[000324] The term "sulfonamide" is recognized in the art and refers to the group represented by the general formulas

wherein R9 and R10 independently represent hydrogen or hydrocarbyl, such as alkyl, or R9 and R10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[000325] The term "sulfoxide" is recognized in the art and refers to the group -S(O)-R10, where R10 represents a hydrocarbyl.

[000326] The term "sulfonate" is art recognized and refers to SO3H, or a pharmaceutically acceptable salt thereof.

[000327] The term "sulfone" is recognized in the art and refers to the group -S(O)2-R10, where R10 represents a hydrocarbyl.

[000328] The term "thioalkyl", as used herein, refers to an alkyl group substituted with a thiol group.

[000329] The term "thioester", as used herein, refers to a group -C(O)SR10 or -SC(O)R10 wherein R10 represents a hydrocarbyl.

[000330] The term "thioether", as used herein, is equivalent to an ether, in which the oxygen is replaced with a sulfur.

em que R9 e R10 independentemente representam hidrogênio ou uma hidrocarbila, tal como alquila, ou qualquer°Corrência de R9 considerados juntamente com R10 eo átomo(s) interveniente completar um heterociclo tendo de 4 a 8 átomos na estrutura do anel.[000331] The term "urea" is recognized in the art and can be represented by the general formula

wherein R9 and R10 independently represent hydrogen or a hydrocarbyl, such as alkyl, or any °R9 occurrence taken together with R10 and the intervening atom(s) completing a heterocycle having from 4 to 8 atoms in the ring structure.

[000332] The term "bioavailability" refers to the fraction of an administered drug that reaches the systemic circulation, one of the main pharmacokinetic properties of drugs. When a drug is administered intravenously, its bioavailability is 100%. When a drug is administered through other routines (such as oral), its bioavailability usually decreases due to incomplete absorption and first-pass metabolism, or it may vary from patient to patient. Bioavailability is a term denoting the measurement of a total amount of drug that reaches the general circulation from an administered pharmaceutical composition, for example, from an orally or intravenously administered pharmaceutical composition, in a single dose or multidose configuration. It is often expressed as %, i.e., area under the "AUC" concentration time curve (from 0 time to infinity) or AUC (from 0 time to 48 or 72 h) of a single dose of drug when administered, by example, orally, in serum, blood, or plasma compared to the AUC (from 0 time to infinity) or AUC (from 0 time to 48 or 72 h) of a single dose of the same amount of drug when injected, i.e., AUC( orally)/AUC(injected) expressed in %. Also, "T max" means the time to reach the maximum plasma concentration (C max) after administration.

[000333] "Protective group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl groups ("TES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS groups or TIPS), glycol ethers such as ethylene glycol and propylene glycol derivatives and allyl ethers.

[000334] As used herein, a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the °Occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[000335] The term "treatment" includes prophylactic and/or therapeutic treatments. The term "prophylactic or therapeutic" treatment is art recognized and includes administering to the host one or more of the subject compositions. If it is administered before the clinical manifestation of the unwanted condition (e.g. disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e. it protects the host against the development of the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment will be therapeutic, (that is, it intends to lessen, improve or stabilize the existing unwanted condition or side effects thereof).

[000336] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into therapeutically active agents, such as compounds of Formula A or Formula B. A common method for preparing a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates (eg, esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present disclosure. Alternatively, amides (e.g. an amide of an amino group) can be a prodrug of the description.

[000337] In certain embodiments, some or all of the compounds of formula I in a formulation depicted above may be replaced with the appropriate corresponding prodrug, for example, where a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.

[000338] One or more constituent atoms of the compounds presented here may be substituted or substituted with isotopes of the atoms in natural or unnatural abundance. In some embodiments, the compound includes at least one hydrogen that is enriched by deuterium atoms, i.e., the compound contains deuterium atoms in excess of the natural abundance of deuterium on earth. For example, one or more hydrogen atoms in a compound shown here may be enriched by deuterium (for example, one or more protium atoms of a C1-6 alkyl group may be replaced by deuterium atoms, such as -CD3 being replaced by a more common-C(1H)3 methyl group). In some embodiments, the compound is enriched by two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, or 24 deuterium atoms. In some embodiments, all hydrogen atoms in a compound can be enriched by deuterium atoms instead of protium atoms.

[000339] Synthetic methods for including isotopes in organic compounds are known in the art (Deutherium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt , Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labeling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds may be used. in various studies such as NMR spectroscopy, metabolism experiments, and/or assays.Substitution with heavier isotopes, such as deuterium for protium, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life requirements dosage ranges, and therefore may be preferred in some circumstances.(See, for example, A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. .Label Compd.Radiopharm. 2015, 58, 308-312).

[000340] The radionuclide that is incorporated into the present radiolabelled compounds will depend on the specific application of that radiolabelled compound. For radioimaging applications, 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br, or 77Br may be useful.

[000341] It is understood that a "radiolabeled compound" or "labelled" is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from 3H, 14C, 125I, 35S and 82Br.

[000342] The present invention may also include synthetic methods for incorporating radioisotopes into the compounds of the description. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one skilled in the art will readily recognize applicable methods for the compounds of the disclosure. pharmaceutical compositions

[000343] In certain embodiments, the description refers to a solid pharmaceutical composition comprising a compound of the description, such as a compound of formula (I) (which includes compounds of formulas (I'), (I''), ( I"'), (I*), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih)) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[000344] In certain embodiments, the present invention relates to a pharmaceutical preparation suitable for use in a human patient, comprising any compound of the description (for example, a compound of formula (I)), and one or more pharmaceutically acceptable excipients . In certain embodiments, the pharmaceutical preparations can be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a pyrogen activity low enough to be suitable for use in a human patient.

[000345] An embodiment of the present invention relates to a pharmaceutical kit comprising a compound of the description, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, and optionally instructions on how to administer the compound.

[000346] The compositions and methods of the present invention can be used to treat an individual in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the description and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, non-aqueous carriers such as glycols, glycerol, oils such as olive oil, or injectable organic esters. Excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in unit dosage form such as a tablet, capsule (including tinted capsule and gelatin capsule), granule, lyophilis for reconstitution, powder, suppository, or the like. The composition can also be present in a transdermal delivery system, for example, a skin patch.

[000347] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility, or enhance absorption of a compound such as a compound of the description. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical preparation or composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymeric matrix, which may have incorporated therein, for example, a compound of the description. Liposomes, for example, which comprise phospholipids or other lipids, are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to make and administer.

[000348] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable risk/benefit ratio.

[000349] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as an encapsulating material, liquid or solid filler, diluent, excipient or solvent. Each vehicle must be "acceptable" in the sense of being compatible with other ingredients in the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) ethyl alcohol; and (17) other non-toxic compatible substances used in pharmaceutical formulations.

[000350] A pharmaceutical composition (preparation) can be administered to an individual by various administration routines including, for example, orally (for example, purgatives as in non-aqueous solutions or suspensions, tablets, capsules (including powdered capsules and gelatine capsules) , cakes, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (eg, sublingually); anally, rectally, or vaginally (eg, as a pessary, cream, or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (eg, as a patch applied to the skin); and topically (for example, as a cream, ointment, or spray applied to the skin, or as an eye drop). The compound can also be formulated for inhalation. Details of proper routes of administration and suitable compositions therefor can be found in, for example, US Patent Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172 .896, as well as the patents cited therein.

[000351] The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect.

[000352] Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent to about 30 percent.

[000353] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the description, with the vehicle and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[000354] Formulations of the invention suitable for oral administration may be in the form of capsules (including powdered capsules and gelatin capsules), seals, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilis, powders , granules, or as a solution or a suspension in a non-aqueous liquid, or as tablets (using an inert base such as gelatin and glycerin, or sucrose and acacia) and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds can also be administered as a cake, elitary, or paste.

[000355] To prepare solid dosage forms for oral administration (capsules (including powdered capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers , such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution delay agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including powdered capsules and gelatine capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[000356] A tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (eg gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycollate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.

[000357] Tablets, and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including powdered capsules and gelatin capsules), pills and granules, can optionally be marked or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes and/or microspheres. They can be sterilized, for example, by filtering through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium just before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

[000358] Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration can be presented as a suppository, which can be prepared by mixing one or more active compounds with one or more excipients or suitable non-irritating vehicles comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

[000359] Alternatively or additionally, the compositions may be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery through such devices can be especially useful for delivery into the bladder, urethra, ureter, rectum, or bowel.

[000360] Formulations that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[000361] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be necessary.

[000362] Ointments, pastes, creams and gels may contain, in addition to an active compound, excipients such as vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid , talc and zinc oxide, or mixtures thereof.

[000363] Powders and sprays may contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons and unsubstituted volatile hydrocarbons such as butane and propane.

[000364] Transdermal patches have the added advantage of providing controlled release of a compound of the present invention to bodies. Such dosage forms can be made by dissolving or dispersing the active compound in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[000365] Ophthalmic formulations, ophthalmic ointments, powders, solutions and the like are also contemplated as being within the scope of this description. Exemplary ophthalmic formulations are described in US Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and US Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to those of tear fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred routine of administration is local administration (eg, topical administration such as eye drops, administration via an implant).

[000366] The phrases "parenteral administration" and "parenterally administered" as used herein mean modes of administration other than parenteral and topical administration, generally by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal injection and infusion , intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal.

[000367] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more sterile isotonic non-aqueous solutions, dispersions, suspensions or emulsions, or pharmaceutically acceptable sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before of use, which may contain antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[000368] Examples of suitable non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include ethanol, polyols (propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters , such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[000369] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antifungal and antibacterial agents, for example, paraben, chlorobutanol, phenol and sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[000370] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished through the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption then depends on its rate of dissolution, which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[000371] The injectable deposit forms are made by forming the microencapsulated matrices of the object compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on a drug to polymer ratio, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by capturing the drug in liposomes or microemulsions that are compatible with body tissue.

[000372] For use in the methods of this invention, the active compounds can be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[000373] Methods of introduction can also be provided by rechargeable or biodegradable devices. Several slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled release of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for sustained release of a compound at a particular target site.

[000374] The actual dosage levels of the active ingredients in the pharmaceutical compositions can be varied in order to obtain an amount of the active ingredient that is effective to obtain the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[000375] The selected dosage level will depend on a variety of factors including the activity of the compound or compound combination employed, the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the compound particular compound(s) being employed, the duration of treatment, other drugs, compounds, and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and past medical history of the patient is being treated, and as factors well known in the medical arts.

[000376] A physician or veterinarian skilled in the art can easily determine and prescribe the therapeutically effective amount of the required pharmaceutical composition. For example, the physician or veterinarian may start doses of the pharmaceutical composition or compound at levels lower than those required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary with the individual's weight, sex, age and medical history. Other factors that influence the effective amount can include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the description. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th ed., 1814-1882, incorporated herein by reference).

[000377] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound which is the smallest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

[000378] If desired, the daily effective dose of the active compound can be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound can be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[000379] The patient who receives this treatment is any animal in need, including primates, in particular humans, and other mammals such as horses, cattle, pigs and sheep; and domesticated birds and pets in general.

[000380] In certain embodiments, the compounds of the description can be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase "joint administration" refers to any form of administration of two or more different therapeutic compounds, such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, different therapeutic compounds can be administered in the same formulation or in a separate formulation, concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual receiving such treatment can benefit from a combined effect of different therapeutic compounds.

[000381] In certain embodiments, co-administration of compounds of the description with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) provides enhanced efficacy relative to each individual administration of the compound of the description (e.g., compound of formula (I)) or the one or more additional therapeutic agents. In certain such embodiments, co-administration provides an additive effect, where an additive effect refers to the sum of each of these effects of individual administration of the compound of the description and the one or more additional therapeutic agents.

[000382] This invention includes the use of pharmaceutically acceptable salts of compounds of the description in the compositions and methods of the present description. The term "pharmaceutically acceptable salt" as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, oxalic, mandelic and others. Pharmaceutically acceptable salt forms may include forms where the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one molecule of inorganic or organic acid per molecule of base base, such as two molecules of hydrochloric acid per molecule of compound of formula (I). As another example, the salt may comprise less than one molecule of inorganic or organic acid per molecule of base, such as two molecules of compound of formula (I) per molecule of tartaric acid.

[000383] In other embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, the L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine salts. , ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

[000384] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such a solvate may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or incidental to such solvent.

[000385] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants may also be present in the compositions .

[000386] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[000387] The invention now being described generally, will be more readily understood by reference to the following examples which are included merely for the purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the description. Examples Abbreviations: ACN = acetonitrile Boc = tert-butyloxycarbonyl Bn = benzyl Cbz or Z = benzyloxycarbonyl COD = cyclooctadiene DCM = methylene chloride or dichloromethane DMAP = 4-(dimethylamino)pyridine DMF = dimethylformamide dppe = ethylenebis(diphenylphosphine) EDC or EDCI = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EtOAc = ethyl acetate iso-BuB(OH)2 = isobutylboronic acid LiHMDS - lithium bis(trimethylsilyl)amide OSu = N-hydroxysuccinimide TBAF = fluoride hydrate of tetrabutylammonium TFA = trifluoroacetic acid THF = tetrahydrofuran TMS = trimethylsilane Z-Ala-OSu = Benzyloxycarbonyl-L-alanine hydroxysuccinimide ester Z-OSu = N-(Benzyloxycarbonyloxy)succinimide Pin = pinacol Example 1: General procedure for the formation of alcoholate complex.

[000388] Boronic acid amino acid (200 mg) was suspended in anhydrous alcohol (20 mL). The suspension was stirred at 70°C for 14 hours, resulting in complete dissolution of the compound. The flow condenser was switched to a small distillation head and the reaction was distilled (at atmospheric pressure (with a Drierite drying tube attached to exclude moisture) until the hot solution began to become cloudy (approximately half the alcohol was collected during the distillation). Anhydrous alcohol (10 mL) was added and then the reaction was heated to 80 °C and stirred at 80 °C for a further 4 hrs. The distillation process was repeated until the solution became cloudy again (~10 mL of distillate collected). Anhydrous alcohol (10 mL) was added again and then the reaction was heated to 80 °C and stirred at 80 °C for a further 2 h. The distillation process was repeated until the solution immediately started to become cloudy (~15 mL of distillate collected). The remaining solution was allowed to cool to room temperature and then filtered and quickly dried by suction, and then also dried under high vacuum (38mTor) at temperature hard environment wait at least 2 hrs to deliver the product as an off-white to light yellow powder. Example 2: Exemplary Synthetic Method for Arginase Inhibitor Synthesis of (6aS,9aR)-8-(L-alanyl)-9a-amino-3-ethoxyoctahydro-[1,2]oxaborocino[6,7-c ]pyrrol-1(3H)-one (10e). isoDrooanol acetonitrile. diethanolamine

[000389] The starting material, compound 21 (racemic), was prepared as described in WO2012/058065 on page 48-50, which is incorporated herein by reference. Resolution was performed by chiral chromatography. Racemic compound 21 was resolved on a chiral stationary phase CHIRALPAK® 1B column (Daicel Chiral Technologies) using heptane-ethanol as the eluent to produce the resolved enantiomer of compound 21. Iridium-catalyzed hydroboration to provide 22

[000390] A 10 L reaction flask with dichloromethane (5 L) was evacuated to approximately 250 mBar, and the pressure was released with nitrogen. The procedure was repeated twice, and the reaction was carried out under a nitrogen atmosphere. Bis(1,5-cyclooctadiene)diridium (I) dichloride (26.00 g, 38.7 mmol, 0.03 eq.) and ethylenebis(diphenylphosphine) (30.85 g, 77.4 mmol , 0.06 eq.) were added, and the mixture was stirred at 13-15°C until formation of a clear solution was observed. Compound 21 (resolved, 466.3 g, 1.269 mol) was added, and the mixture was stirred at 15-17°C for a period of 30 minutes. The resulting dark red solution was cooled to 0 °C, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (224.0 g, 1.750 mol, 1.38 eq.) was added at -2 at +2°C for a period of one hour. The reaction mixture was stirred at -2 to +2°C for a period of 2 hours, and HPLC indicated 90.7% conversion. After stirring an additional 14 h at 18-22 °C, HPLC indicated 98.9% conversion.

[000391] Acetonitrile (2.2 L) was added to the reaction mixture. The mixture was heated to distillation at 30-35°C under reduced pressure (470 mBar), and 2.7 L was distilled. Acetonitrile (2.2 L) was added to the residue. The mixture was heated to distillation at 35-38°C under reduced pressure (350-250 mBar), and 2.2 L was distilled. Acetonitrile (2.2 L) was added to the residue. The mixture was heated to distillation at 55-40°C under reduced pressure (240-155 mBar), and 3.7 L was distilled.

[000392] The residual suspension (~1300 ml) was stirred at 20-23°C overnight and the precipitate was isolated by filtration. The filter cake was washed with cold (0-10°C) acetonitrile (1.5 L) and dried to constant weight at 40°C in a ventilated drying oven. Obtained yield of compound 22: 466.5 g (74%). Compound Preparation 26

[000393] 48% HBr (aq., 500 mL) and compound 22 (250 g, 505 mmol) were added to a 2 L 3-neck round bottom flask. The mixture was heated for distillation, and the distillation was continued until an internal temperature of 120°C was obtained. The mixture was stirred at 120 °C for a further 2 h. The mixture was allowed to cool to room temperature. Water was added (0.5 L), and the reaction mixture was extracted with toluene (1 L). The atmosphere was exchanged for nitrogen and the aqueous mixture was cooled to 0°C, and the aqueous solution of compound 23 was left overnight. The pH of the mixture was adjusted to 9.7 with NaOH (27.65%, 460 mL), followed by the addition of acetonitrile (750 mL). Z-Ala-OSu (323 g, 1009 mmol, 2 eq.) was added, and pH was continuously adjusted to 9.5-10.0 with NaOH (27.65%, 175 mL). After 1.5 h, conversion was >98% (TLC). The pH was adjusted to 3.3 with 48% HBr (aq., 207 mL), and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with toluene (1.14 L) and twice with ethyl acetate (2 x 1.14 L). The two ethyl acetate layers were back extracted twice with water (2 x 225 mL). The combined aqueous phases, containing compound 24, were kept under nitrogen at 0°C overnight.

[000394] The pH of the mixture was adjusted to 10.4 with NaOH (27.65%, 207 mL), and the temperature was allowed to rise to 10-20°C. Acetonitrile was added (750 mL), followed by Z-OSu (176 g, 707 mmol, 1.4 eq.) and the pH of the mixture was continuously adjusted to 10.0-10.5 with NaOH (27.65%, 112 mL). The reaction was allowed to continue for 3 h until >95% conversion was observed (HPLC, comparison with standard). The pH was adjusted to 3.2 with 48% HBr (aq., 300 mL). Ethyl acetate (1.14 L) was added, and the mixture was stirred vigorously. The phases were separated and the organic phases combined refer to the addition of compound 25 which was kept in the freezer overnight.

[000395] The ethyl acetate solution of compound 25 was evaporated under reduced pressure in a water bath temperature of 50°C to dryness. Acetonitrile (200 mL) was added, and evaporation was continued to dryness. The residue was dissolved in acetonitrile (3.63 L) at 40°C and isopropanol (225 mL) was added. Diethanolamine (95.9 g, 912 mmol) was dissolved in isopropanol (150 mL) and acetonitrile (150 mL). The diethanolamine solution was added to the acetonitrile/isopropanol solution of compound 25 at 40°C for 10 minutes. The solution was seeded with compound 26 and cooled to room temperature. Precipitation was very low and had to be left overnight where a thick suspension was obtained. The suspension was filtered slowly, and the filter cake was washed with 2 L of 10% isopropanol/acetonitrile. Part of the filter cake was dried, giving a yield of 83% (276.2 g).

[000396] Most of the material (271.6 g) was reprecipitated by suspending it in isopropanol (400 mL) and acetonitrile (900 mL). The solid was dissolved at reflux temperature. Acetonitrile (2.7 L) was added, and the solution was allowed to cool to room temperature. At 45°C precipitation was observed. After 5 h, the slurry was filtered and the filter cake was washed with 1.5 L of isopropanol / 10% acetonitrile. The solid was dried overnight in vacuo at 25°C, yields 239.2 g of compound 26 (88% recovery, 72% overall yield). Preparation of Compound 10e

[000397] To a 5 L three-neck round bottom flask were added water (2.4 L) and 36% HCl (aq, 75 g). Ethyl acetate (2.45 L) was added followed by compound 26 (250 g, 343 mmol). The mixture was stirred until the solid dissolved. The phases were separated, and the aqueous phase was extracted with ethyl acetate (1.22 L). The combined organic phases were dried over magnesium sulfate (190 g). The suspension was filtered, and the filter cake was washed with ethyl acetate (560 mL). The filtrate and wash were evaporated under reduced pressure in a water bath temperature of 50°C to give crude 25 as a white foam. Ethanol (2.4 L) and water (100 mL) were added, and the mixture was stirred until a solution was obtained. The system was evacuated to <180 mbar and the vacuum was released with nitrogen three times. 10% Pd/C was added (moisture, 57.7% water, 35.9 g). The system was evacuated to <180 mbar and the vacuum released with nitrogen once and hydrogen three times. The hydrogenation was continued overnight at room temperature, then the atmosphere was exchanged for nitrogen and another portion of 10% Pd/C was added (moisture, 57.7% water, 4.5 g). The atmosphere was exchanged for hydrogen, and the hydrogenation was continued overnight. The suspension was filtered over celite (83g), and the filter cake was washed with a mixture of ethanol (400ml) and water (16.7ml) to give a crude solution of 10. The filtrate was evaporated under reduced pressure over portions in a water bath temperature of 50°C to a volume of 350-400 mL. Ethanol (600 mL) was added, and the solution was seeded with compound 10e. The fine suspension was concentrated to the same volume under reduced pressure and at a water bath temperature of 50°C. The suspension was kept at -15°C for three days. The suspension was allowed to warm to about 0°C and then filtered (GF-A). The filter cake was washed with ethanol (3 x 100 mL). The solid was dried at 50°C under vacuum overnight to provide 82.8g of compound 10e. This material could also be purified as described below.

[000398] Compound 10e (77.5 g) was suspended in ethanol (1.1 L) and heated to 60-62 °C for 6 h and 15 min. The suspension was cooled to 2°C, and stirred overnight. The suspension was filtered and the filter cake was washed with ethanol (400 mL). The solid was dried at 50°C under vacuum overnight to provide 71.5 g of compound 10e as a white solid.

[000399] An analytical sample or 10e was prepared as follows: 2g of 10e were suspended in sufficient anhydrous ethanol (~70 mL) to fully dissolve the material at 80°C. This solution was heated at 80°C for 2 hrs under an atmosphere of dry nitrogen. The reflux condenser was switched to a small still head and a reaction was distilled (at atmospheric pressure, with a drying tube attached to exclude moisture) until the hot solution began to become cloudy (approximately 40 mL of ethanol was collected during distillation). This process was repeated twice more, and the remaining solution was allowed to cool to room temperature and then filtered and quickly sucked dry, and then also dried under high vacuum (40 mTor) at room temperature for 2 hrs to give a sample. analytical strength of 10e as a white powder.

[000400] Compound 10e. 400MHz, d6-DMSO: (3:2 rotamer population) d 7.01-6.80 (2H, br m, exch), 3.81 (1H, d, J = 12.8 Hz), 3.68 (0.6H, dd, J = 9.8, 7.5Hz), 3.62 (0.4H, dd, J = 11.3, 7.8Hz), 3.53 (0.4H, d, J = 10.4 Hz), 3.48-3.35 (3H, m), 3.20 (0.6 H, d, J = 12.5 Hz), 3.13 (0.6H, dd, J = 11.7, 9.7 Hz), 2.81 (0.4H, t, J = 11.6 Hz), 2.42 (0.6H, m) and 2.30 (0.4H, m ), 1.83-1.70 (2H, m), 1.62 (2H, br s, exch), 1.44-1.37 (1H, m), 1.09-1.04 (6H, m, CH3CH2 and CH3CHN), 0.98 (1H, dd, J = 15, 12.4 Hz), 0.65 (1H, dd, J = 14.7, 5.6 Hz) and 0.42 (1H , m). 11B-NMR (400 MHz, DMSO) δ 7.85 ppm. FTIR (powder diffraction) (cm-1): 2905 (w), 1722 (s), 1646 (s), 1623 (s), 1271 (s), 1119 (s), 1067 (m), 658 (m ) and 562 (m).

[000401] 800 mg of the analytical sample of 10e were dissolved in a minimum amount of ethanol (~30 mL) at room temperature. This solution was allowed to stir, at room temperature and pressure, in a desiccator, fitted with a DRIERITE® drying tube to exclude moisture, to allow the ethanol to slowly evaporate, causing fine crystals to slowly form over the course of 10 days. These crystals were suction filtered, washed quickly with cold (5°C) ethanol and then dried under high vacuum (40 mTor) at room temperature for 14 hrs to yield the product (386 mg) as white crystals suitable for crystallography. X-ray structure determination

[000402] Low temperature diffraction data (w-scans) were collected on a Rigaku MicroMax-007HF diffractometer coupled to a Saturn994+ CCD detector with Cu Kα (À = 1.54178 Â) for the 10e structure. Diffraction images were processed and scaled using Rigaku CrystalClear software (CrystalClear and CrystalStructure; Rigaku/MSC: The Woodlands, TX, 2005). The structure was solved with SHELXT and refined against F2 on all data by full matrix least squares with SHELXL ( Sheldrick, G.M. Acta Cryst. 2008, A64, 112-122 ). All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model in geometrically calculated positions and refined using a riding model. The isotropic shift parameters of all hydrogen atoms were set to 1.2 times the U value of the atoms to which they are bonded (1.5 times for methyl groups). All hydrogen atoms associated with nitrogen atoms were found in the difference map. The N-H distances were restricted to 0.92(2) as suggested by the difference map. Atomic shift parameters were left to refine freely. The hydrogen atom associated with ethanol was geometrically placed and constrained. All hydrogen atoms involved in hydrogen bonding were identified and their metrics associated with the donor/acceptor were refined.

[000403] The structure of 10e obtained by X-ray diffraction is shown in FIG. 1 to 50% thermal ellipsoid probability levels. This structure is consistent with the 10e line drawings shown in the text. Certain crystal and structure refinement data for 10e are provided in Table 2. Table 2. Crystal and structure refinement data for 10e.

[000404] The conversion of compound 10 into compound 10e represents an equilibrium and the composition of the mixture depends on the solvent composition. Formation of 10e°Corre on treatment of compound 10 with anhydrous ethanol. This transformation presumably proceeds through intermediates B and/or C as shown in Scheme 1. Compound 10e is the predominant species formed by treating 10 with absolute ethanol and removing water via distillation or resuspending the material with pure absolute ethanol. Samples of 10 that have undergone less extensive processing (in ethanol) to remove water contain mixtures of 10e and intermediates A, B, or C (Scheme 1). Scheme 1. Interconversion of compounds 10 and 10e.

[000405] The isolated ethanolate (compound 10e) rapidly hydrolyses under physiological conditions or any other aqueous conditions into the open form of free boronic acid, compound 10, which can exist in an equilibrium of open form A and closed form B. It should be understood In these described structures, each of the NH2 moieties exists in a balance of protonated (salt) and unprotonated (free base) forms, and the above descriptions are not intended to represent a fixed form of either of these moieties. The presence of other acids and/or bases in a solution will affect these equilibria, as will be understood by those skilled in the art.

[000406] The rapid conversion of compound 10e to compound 10 in water was confirmed by the similarity of a spectrum of 10e in D2O to a spectrum of 10 in D2O. When a sample of compound 10e was dissolved in D2O and the spectra immediately recorded (time taken <5 minutes), the observed spectra are identical to the spectra of compound 10 (the free boronic acid) plus ethanol (1:1 ratio). The spectrum of 10e in D2O was the same at 5 minutes and one hour after sample preparation, indicating that the transformation was rapid and complete after a few minutes.

[000407] FIG. 2 demonstrates the conversion of 10e to 10 in D2O. The A-labeled NMR (D2O) spectra are compound 10 (free base) prepared from 11 as described in Example 2. The B-labeled NMR (D2O) spectra are an analytical sample of compound 10e prepared as described above. The NMR (D2O) spectra labeled C are sample B spectra that were freeze-dried and redissolved in D2O. The spectra in FIG. 2 demonstrate that 10e undergoes hydrolysis in water and the spectra of 10e in D2O are identical to 10, except for the presence of ethanol, which is released in hydrolysis.

[000408] Upon dissolution in 1:1 water/acetonitrile and immediate injection into an HPLC system, only a single peak is observed. The mass of this peak is consistent with compound 10. No mass is observed for intact compound 10e.

Ácido trans-4-alil-3-azido-1-(terc-butoxicarbonil)pirrolidina-3-carboxílico (4, racemic)

[000409] Compound 10 is hygroscopic, with consistent water uptake when humidity is increased. Observed moisture uptake is greater than 70% to 90% relative humidity (RH). The sorption and desorption isotherms show minimal hysteresis for compound 10. Compound 10e is not remarkably hygroscopic under conditions below 60% RH. The sorption isotherm suggests that compound 10e does not absorb water up to 40 weight percent between 60 and 90% RH. The isotherm also indicates significant hysteresis. This hysteresis is consistent with the rapid hydrolysis of the ethanolate to the corresponding boronic acid form which has associated water in the solid state when isolated in solutions containing water. Example 3: Alternative Synthesis of an Exemplary Arginase Inhibitor (3R, 4S)-3-amino-1-((S)-2-aminopropanoyl)-4-(3-boronopropyl)-yl)pyrrolidine-3-carboxylate .

trans-4-allyl-3-azido-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (4, racemic)

[000410] A solution of chloroform (26.86 mL, 333 mmol) and TMS-Cl (32.86 mL, 257.1 mmol) in anhydrous THF (300 mL) was cooled to -78°C. After stirring for 10 min, LiHMDS (1M in THF, 249 mL, 249 mmol) was added at a rate such that the temperature was maintained below -60 °C (approximately 30 min). After stirring for a further 30 min at -60 to -70 °C (reaction mixture became cloudy) the solution was warmed to -20 °C (reaction mixture became clear) and treated with tert-butyl-3-allyl- 4-oxopyrrolidine-1-carboxylate (3.30 g, 133.2 mmol) in DMF (90 mL) and tetrabutylammonium acetate (3.69 g, 12.24 mmol) in DMF (90 mL) at a rate of so that the internal temperature remained below -20°C (reaction mixture became cloudy). After the addition was complete, the reaction mixture was warmed to room temperature with stirring until the acetone starting material was consumed (by TLC), then poured into saturated aqueous NH 4 Cl and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed successively with saturated aqueous NH 4 Cl and saturated aqueous NaCl (2 x 80 mL), dried over MgSO 4 , filtered and concentrated.

[000411] While under nitrogen, the crude TMS-protected intermediate was dissolved in dry THF (300 mL), cooled to 0 °C and carefully treated with acetic acid (7.5 mL, 130.9 mmol) and TBAF (1 M in THF, 133.2 mL, 133.2 mmol) dropwise. After the addition was complete, the reaction was stirred for an additional 10 min at 0 °C then poured into saturated aqueous NaHCO 3 and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO 4 , filtered and concentrated to free the crude alcohol intermediate.

[000412] The crude alcohol was dissolved in dioxane (200 mL), cooled to 0°C, and treated with a precooled (0°C) solution of sodium azide (14.04 g, 399.5 mmol) and NaOH (15.98 g, 399.5 mmol) in water (200 mL) dropwise. The resulting reaction mixture was allowed to warm to room temperature with stirring overnight then quenched with saturated aqueous NH 4 Cl and extracted with EtOAc (500 mL). the aqueous layer was separated and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with water and saturated aqueous NaCl, dried over MgSO 4 , filtered and concentrated to give crude trans-4-allyl-3-azido-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (4, raw 45g) which was used without further purification. 1H-NMR (CDCl3, 400 MHz): δH : 5.80 (1H, m), 5.06 (2H, m), 4.05 (1H, dd, J = 9.9, 4.9 Hz), 3.59 (2H, m), 3.22 (1H, dd, J = 11.6, 4.4 Hz), 3.08 (1H, dd, J = 11.0, 5.2 Hz), 2 .24-2.04 (2H, m), 1.65 (1H, br s, OH) and 1.45 (9H, s). trans -3-Benzyl-1-(tert-butyl)-4-allyl-3-azidopyrrolidine-1,3-dicarboxylate

[000413] A solution of crude trans-4-allyl-3-azido-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (4, 39.5 g, 133 mmol - amount calculated assuming 100% production from previous steps) and K2CO3 (92.04 g, 666 mmol) in acetonitrile (317 mL) was cooled to 0 °C and treated with benzyl bromide (17.52 mL, 146.5 mmol). After stirring overnight at room temperature, the solution was concentrated, dissolved in EtOAc (600 mL), washed with saturated aqueous NaCl, dried over MgSO 4 , filtered and concentrated. Purification by silica gel chromatography (10 to 30% EtOAc in hexane) provided trans-3-benzyl-1-(tert-butyl)-4-allyl-3-azidopyrrolidine-1,3-dicarboxylate as yellow liquid (5.40 g, 78% yield).

[000414] The product was separated into its enantiomers using a Chiral Technologies Chiralpak ADH column with isopropyl alcohol and hexanes (2:98) as an eluent. Analysis of the separated enantiomers using a Chiralpak ADH analytical column (4.6 x 250 mm) with the same eluent and a flow rate of 1.0 mL/min and UV detection (210 nm) provided the desired enantiomer (3-benzyl -1-(tert-butyl)(3R,4S)-4-allyl-3-azidopyrrolidine-1,3-dicarboxylate, 5a) with a retention time of 13.5 min and the undesired enantiomer (3-benzyl-1 -(tert-butyl)(3S,4R)-4-allyl-3-azidopyrrolidine-1,3-dicarboxylate, 5b) at 10.3 min, each with an enantiomeric excess of approximately 98%. 1H-NMR (CDCl3, 400 MHz): δH : 7.37 (5H, s), 5.62 (1H, m), 5.25 (2H, m), 5.00 (2H, m), 3.88 (1H, m). dd, J = 37.2, 12.0 Hz), 3.58 (1H, ddd, J = 37.2, 11.0, 7.0 Hz), 3.42 (1H, dd, J = 21, 4, 12.0 Hz), 3.28 (1H, ddd, J = 28.3, 11.0, 5.4 Hz), 2.41 (1H, m), 2.11 (1H, m), 1.80 (1H, m) and 1.44 (9H, s). 1-tert-butyl 3-azido-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1,3-dicarboxylate ( 3R,4S)-3-benzyl (6)

[000415] To a stirred solution of 3-benzyl-1-(tert-butyl) (3R,4S)-4-allyl-3-azidopyrrolidine-1,3-dicarboxylate (5a, 16.4 g, 42.4 mmol) in anhydrous methylene chloride (130 mL) under a nitrogen atmosphere was treated with bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.75 g, 1.12 mmol) and 1 ,2-bis(diphenylphosphino)ethane (0.894g, 2.24mmol) and the reaction was stirred for 30 minutes at room temperature and then cooled to -25°C. 4,4,5,5-tetramethyl[1,3,2]dioxaborolane (9.83 mL, 67.75 mmol) was added dropwise and then the reaction was allowed to warm slowly to room temperature and stirred for 20 hrs . Water (60 mL) was added and the reaction was stirred for 10 minutes, then the methylene chloride was removed under reduced pressure. The remaining aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual solid was passed through a short pad of silica, eluting with 15% to 30% ethyl acetate in hexane, to provide 3-azido-4-(3-(4,4,5,5-tetramethyl-1 (3R,4S)-3-Benzyl 1-tert-butyl,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1,3-dicarboxylate (6, 12.5 g, 57%). 1H-NMR (CDCl3, 400 MHz): δH : 7.35 (5H, m), 5.23 (2H, m), 3.85 (1H, dd, J = 39.3, 11.8 Hz), 3.60 (1H, m), 3.37 (1H, dd, J = 24.3, 11.8 Hz), 3.25 (1H, ddd, J = 40, 10.6, 6.6 Hz) , 2.33 (1H, m), 1.43 (9H, s), 1.39-1.26 (3H, m), 1.21 (12H, s), 1.07 (1H, m) and 0.68 (2H, m). (3R,4S)-3-Benzyl-3-azido-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxylate, trifluoroacetic acid salt (7).

[000416] A solution of 3-azido-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1,3-dicarboxylate (3R,4S)-3-benzyl 1-tert-butyl (6, 10.2 g, 19.8 mmol) was dissolved in anhydrous methylene chloride (160 mL), cooled to 0 °C and treated with trifluoroacetic acid ( 40 mL). The reaction mixture was then allowed to warm up, stirred at room temperature for 4 hr and then concentrated under reduced pressure to give a viscous oil. The resulting oil was azeotroped with dry toluene (3 x 100 mL) to remove residual trifluoroacetic acid and then dried under high vacuum to afford (3R,4S)-3-benzyl-3-azido-4-(3-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxylate, trifluoroacetic acid salt (7) as a very viscous oil (10.56 g), which slowly it becomes a glass. 1H-NMR (CDCl3, 400 MHz): δH : 9.7 (1H, br m (exch), NH), 7.55 (1H, br s (exch), NH), 7.38 (5H, m) , 5.31 (1H, d, J = 11.7 Hz), 5.26 (1H, d, J = 11.7 Hz), 3.77 (1H, d, J = 12.5 Hz), 3 .65 (1H, dd, J = 11.8, 7.8 Hz), 3.32 (1H, d, J = 12.4 Hz), 3.18 (1H, m), 2.54 (1H, m), 1.45-1.26 (3H, m), 1.22 (12H, s), 1.02 (1H, m) and 0.63 (2H, t, J=7.4 Hz). (3R,4S)-benzyl-3-azido-1-((S)-2-((tert-butoxycarbonyl)amino)propanoyl)-4-(3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxylate (8).

[000417] A solution of the TFA salt of (3R, 4S)-benzyl-3-azido-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) propyl)pyrrolidine-3-carboxylate (7) (31.43 g, 59.48 mmol) in anhydrous dichloromethane (400 mL) was stirred at room temperature under an atmosphere of dry nitrogen. Triethylamine (33.1 mL, 237.9 mmol), DMAP (200 mg, 1.64 mmol) and HOBt (200 mg, 1.49 mmol) were added and then the reaction mixture was cooled to 0°C. Boc-L-Alanine (16.88 g, 89.22 mmol) was added as a solid in one portion, and then EDCI (17.1 g, 89.22 mmol) was added in 3 portions at 0°C. The reaction mixture was stirred at 0 °C for 1 hour and then allowed to warm to room temperature and stirred overnight at this temperature.

[000418] The reaction mixture was poured into 300 mL of saturated ammonium chloride solution, separated and then the aqueous phase was extracted (3 x 100 mL) with dichloromethane. The combined organic phase was washed with water (200 mL), brine (2 x 200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The reaction was purified on silica gel, eluting with a gradient of ethyl acetate (20-50%) in hexane, to give the title compound (8) as a colorless oil (30.10g, 51.41 mmol, 86%) as a mixture of rotamers. 1H-NMR (400 MHz, CDCl3) δ: 7.3 (5H, s), 5.35 (1H, dd, J=13.5, 8 Hz, NH), 5.25 (2H, m), 4 .35 (1H, m), 4.12-3.30 (4H, m), 2.42 (1H, m), 1.45 (9H, s), 1.37-1.18 (18H, including (3H, d, J = 6.5 Hz) and 1.22 (12H, s)), 1.07 (1H, m) and 0.68 (2H, m), LCMS (ESI +ve): C29H44BN5O7 m /z calculated 585.33, found 586.5 (MH+), 530.5 (MH+ -iBu), 486.5 (MH+ - Boc). (3R,4S)-benzyl-1-((S)-2-aminopropanoyl)-3-azido-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)propyl)pyrrolidine-3-carboxylate, TFA salt (9).

[000419] A solution of (3R, 4S)-benzyl-3-azido-1-((S)-2-((tert-butoxycarbonyl)amino)propanoyl)-4-(3-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxylate (8) (30.04 g, 51.31 mmol) in anhydrous dichloromethane (250 mL) was cooled to 0°C and then a solution of TFA (50 mL) in dichloromethane (50 mL) was added dropwise over 10 minutes. The solution was allowed to warm to room temperature and then stirred at this temperature for 3 hours, until TLC showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to give a light yellow oil. This oil was dissolved in toluene (100 mL) and concentrated. The azeotropic procedure was repeated three times to give the product, as the TFA salt, (30.85 g) as a pale yellow oil. 1H-NMR (400 MHz, D4-MeOH) δ: 7.39 (4H, m), 7.15 (1H, m), 5.29 (2H, dd, J=14, 12 Hz), 4.25 -3.20 (5H, m), 2.51 (1H, m), 1.50-1.25 (6H, including 1.47 (1.5H, d, J = 7.0 Hz) and 1. 31 (1.5H, d, J = 6.9 Hz (alanine rotamers))), 1.20 (12H, s)), 1.07 (1H, m) and 0.65 (2H, m). LCMS (ESI +ve): C24H36BN5O5 m/z calculated 485.3, found 486.2 (MH+). (3-((3S, 4R)-1-((S)-2-aminopropanoyl)-4-azido-4-((benzyloxy)carbonyl)pyrrolodin-3-yl)propyl)boronic acid hydrochloride salt (11 HCl).

[000420] The TFA salt of (3R, 4S)-benzyl-1-((S)-2-aminopropanoyl)-3-azido-4-(3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxylate (9) (30.76 g, 51.31 mmol), was dissolved in a biphasic mixture of methanol (200 mL) and hexane (400 mL) . Isobutylboronic acid (18.31 g, 179.6 mmol) and then 2N hydrochloric acid (50.85 mL, 101.7 mmol) were added. The reaction mixture was stirred vigorously at room temperature for 16 hours. The methanol phase was separated and washed with hexane (5 x 100 mL) and then concentrated in vacuo to give the boronic acid (11 HCl), as a hydrochloride salt, as an off-white foam. 1H-NMR (400 MHz, D2O) δ: 7.48-7.42 (5H, m), 5.31 (2H, m), 4.22 (1H, dd, J=13, 6.5 Hz) , 3.95-3.10 (4H, m), 2.71-2.51 (1H, m), 1.40-1.25 (3H, m), 1.25 - 0.98 (4H, m). m including 1.20 (1.5H, d, J = 6.9 Hz) and 1.07 (1.5H, d, J = 6.9 Hz (alanine rotamers))) and 0.69 (2H, m). LCMS (ESI +ve): C18H26BN5O5 m/z calculated 403.2, found 404.2 (MH+). (3-((3S, 4R)-1-((S)-2-aminopropanoyl)-4-azido-4-((benzyloxy)carbonyl)pyrrolodin-3-yl)propyl)boronic acid (11).

[000421] The acid hydrochloride salt (3-((3S, 4R)-1-((S)-2-aminopropanoyl)-4-azido-4-((benzyloxy)carbonyl)pyrrolodin-3-yl )propyl)boronic (11 HCl), from the previous step, was dissolved in 30 mL of water and then the pH of the solution was adjusted to pH 9 by the careful addition of solid potassium carbonate. The resulting solution was saturated with the addition of solid sodium chloride and then extracted with dichloromethane (5 x 100 mL). The combined dichloromethane phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford product 11, as its free base, as a white foamy solid (19.4 g, 48.11 mmol, 94%). 1H-NMR (400 MHz, D4-MeOH) δ: 7.44-7.36 (5H, m), 5.31 (1H, d, J = 1.8Hz), 5.27 (1H, d, J = 1.8Hz) 4.05 (1H, dd, J = 12.5 Hz), 3.80 (1H, m), 3.69-3.55 (2H, m), 3.45-3.30 (1H, m), 2.51 (1H, m), 1.40-1.05 (7H, m, including 1.22 (1.5H, d, J = 6.8 Hz) and 1.07 ( 1.5H, d, J = 6.8 Hz (alanine rotamers))) and 0.63 (2H, m). LCMS (ESI +ve): C18H26BN5O5 m/z calculated 403.2, found 404.7 (MH+). (3R,4S)-3-amino-1-((S)-2-aminopropanoyl)-4-(3-boronopropyl)-yl)pyrrolidine-3-carboxylate (10).

[000422] The azido benzyl ester, acid (3-((3S,4R)-1-((S)-2-aminopropanoyl)-4-azido-4-((benzyloxy)carbonyl)pyrrolodin-3- yl)propyl)boronic 11 (9.70 g, 24.06 mmol) was suspended in a mixture of water (300 mL) and ethyl acetate (30 mL) and stirred vigorously. 10% Palladium on charcoal (2.6g, 0.1 eq) was added and then the stirred mixture was evacuated under low vacuum, and stimulated with hydrogen. The evacuation/stimulation procedure was repeated 3x to remove air and exchange it with hydrogen and then the reaction was shaken vigorously overnight at room temperature under a hydrogen balloon, at which time, LCMS analysis of the filtered aliquot showed complete reduction of the azide and benzyl ester groups. The reaction mixture was placed under vacuum to remove hydrogen and then stimulated with nitrogen, filtered through a celite pad (with 3 water washes) and then the solution was concentrated to approximately 50 mL in vacuo. The resulting aqueous solution was filtered through a 4 micron filter (to remove trace Pd) and then concentrated in vacuo to afford the title compound 10 as a white powder (6.45 g, 93%), 1H-NMR (400 MHz, D2O) δ 4.12 (1H, m), 4.05 (1H, m), 3.92 (1H, m), 3.60-3.22 (2H, m), 2.47-2 .18 (1H, m), 1.58-1.31 (6H, m including 1.46 (3H, d, J = 6.9 Hz)), 1.24-1.19 (1H, m) and 0.79 (2H, m). LCMS (ESI +ve): C11H20BN3O5 m/z calculated 287.2, found 269.9 (MH+ - H2O), 251.9 (MH+ - 2H2O) and (ESI -ve): C11H20BN3O5 m/z calculated 287.2, found 267.7 (M-H-H2O).

[000423] The conversion of 10 to ethanolate 10e is as described in Example 1, above. (3R,4S)-3-amino-1-((S)-2-aminoacetyl)-4-(3-boronopropyl)-yl)pyrrolidine-3-carboxylate (12) and (6aS,9aR)-8-( 2-aminoacetyl)-9a-amino-3-ethoxyoctahydro-[1,2]oxaborocino[6,7-c]pyrrol-1(3H)-one 12e.

[000424] Compound 12 was prepared as described for 10 in Example 2, using Boc glycine as a coupling partner with 7. Compound 12 (1.0g, 3.7 mmol) was suspended in sufficient anhydrous ethanol (~40 mL ) to fully dissolve the material at 80oC. This solution was heated at 80°C for 2 hrs under an atmosphere of dry nitrogen. The reflux condenser was switched to a small still head and the reaction was distilled (at atmospheric pressure, with a DRIERITE® drying tube attached to exclude moisture) until the hot solution began to become cloudy (approximately 20 mL of ethanol were collected during distillation). Anhydrous ethanol (20 mL) was added and then the reaction was heated to 80 °C and stirred at 80 °C for a further 4 hrs. The distillation process was repeated until the solution became cloudy (~20 mL of distillate collected). This was repeated one more time and the suspension was allowed to cool to RT. The solid was filtered and quickly sucked dry, then also dried under high vacuum (38mTor) at room temperature for 2 hrs to give the product as an off-white powder (986mg) as a 2:1 mixture of rotamers. 1H-NMR (400 MHz, d6-DMSO (2:1 rotamer population)) δ 6.73-7.31 (4H, exch), 3.84 (1H, m), 3.573.71 (3H, m) , 3.48-3.21 (3H, m), 3.05 (0.67 H, dd, J = 11.8, 9.7 Hz), 2.88 (0.33H, t, J = 11.5 Hz), 2.48-2.35 (1H, m), 1.67-1.83 (2H, m), 1.52-1.41 (1H, m), 1.09-1 .03 (3H, m), 0.97 (1H, m), 0.67 (1H, dd, J=14.9, 5.6 Hz, BCHH) and 0.42 (1H, m, BCHH), 11B-NMR (400 MHz, DMSO) δ 7.78 ppm. FTIR (powder diffraction) (cm-1): 2912 (w), 1720 (s), 1645 (s), 1463 (s), 1269 (s), 1102 (s), 1063 (m), 1037 (m ), 660 (s) and 573 (s). Example 4: Exemplary Cyclic Alcoholates

Exemplo 5: Síntese de Compostos Selecionados da Invenção (6aS, 9aR)-9a-amino-8-((S)-2-amino-3-hidroxipropanoil)-3-etoxiocta- hidro-[1,2]oxaboro-cino{6,7-c}pirrol-1{3H}ona (Ri = CH2OH, R2 = Et).

[000425] The following compounds were prepared as in Example 1 (i.e., the conversion of 10 to 10e) by heating with the corresponding anhydrous alcohol under conditions that removed water, such as azeotropic distillation:

Example 5: Synthesis of Selected Compounds of the Invention (6aS, 9aR)-9a-amino-8-((S)-2-amino-3-hydroxypropanoyl)-3-ethoxyoctahydro-[1,2]oxaboro-cyno{ 6,7-c}pyrrol-1{3H}one (Ri = CH2OH, R2 = Et).

[000426] (6aS, 9aR)-9a-Amino-8-((S)-2-amino-hydroxypropanoyl)-3-ethoxyoctahydro-[i,2]oxaborocino{6,7-c}pyrrol-ion {3H}one (Ri = CH2OH, R2 = Et) was prepared according to the general procedure using serinamide (3R, 4S)-3-amino-i-((S)-2-amino-3-hydroxypropanoyl)- 4-(3-Boronopropyl)-yl)pyrrolidine-3-carboxylate as the starting material and ethanol as the alcohol solvent, and was isolated as a light yellow powder, 1 H-NMR (400 MHz, d6-DMSO (3: 2 rotamer population)) δ 6.86-6.97 (2H, exch), 3.84 (2H, m), 3.60-3.68 (iH, m), 3.48-3.35 ( 4H, m), 3.22 (iH, m), 3.ii (0.6H, dd, J = ii.2, i0.4 Hz) and 2.80 (0.4H, t, J = 11, 6 Hz), 2.36 (0.6H, m) and 2.31 (0.4H, m), 1.83-1.65 (2H, m), 1.481.36 (1H, m), 1. 08-1.03 (3H, m, CH3CH2O), 0.96 (1H, m), 0.64 (1H, dd, J=14.0, 4.5 Hz, BCHH) and 0.41 (1H, m, BCHH), 11B-NMR (400 MHz, DMSO) δ7.62 ppm. FTIR (powder diffraction) (cm-1): 1627 (s), 1459 (m), 1365(m), 1063 (s), 589 (m). (6aS, 9aR)-9a-amino-8-((S)-2-aminopropanoyl)-3-isopropoxyoctahydro-[1,2]oxaborocino{6,7-c}pyrrol-1{3H}one (R1 = Me, R2 = i-Pr).

[000427] (6aS, 9aR)-9a-Amino-8-((S)-2-aminopropanoyl)-3-isopropoxyoctahydro-[1,2]oxaborocino{6,7-c}pyrrole-1{ 3H}one (R1 = Me, R2 = Et) was prepared according to the general procedure using alaninamide (3R, 4S)-3-amino-1-((S)-2-aminopropanoyl)-4-(3- boronopropyl)-yl)pyrrolidine-3-carboxylate as the starting material and 2-propanol as the alcohol solvent, and was isolated as a light yellow powder, 1H-NMR (400 MHz, d6-DMSO (3:2 population of rotamer)) δ 6.64-6.87 (2H, exch), 3.73-3.81 (1H, m), 3.56-3.66 (1H, m), 3.37-3.49 (2H, m), 3.16 (1H, d, J = 12.9 Hz), 3.10 (0.6H, dd, J = 10.8, 9.6 Hz) and 2.78 (0. 4H, t, J = 11.6Hz), 2.43 (0.6H, m) and 2.31 (0.4H, m), 1.69 (2H, m), 1.40 (1H, m) , 1.07 (3H, d, J = 6.9 Hz, CH3CHO), 1.02 (3H, m), 1.00 (3H, d, J = 6.1 Hz, CH3CHO), 0.95 ( 1H, m), 0.55 (1H, dd, J = 14.7, 5.6 Hz, BCHH) and 0.38 (1H, m, BCHH). 11B-NMR (400 MHz, DMSO) δ8.24 ppm. FTIR (powder diffraction) (cm-1): 1723 (s), 1618 (s), 1459 (s), 1269 (s), 1129 (s), 1074 (m), 653 (m) and 579 (m ). (6aS, 9aR)-9a-amino-8-((S)-2-aminopropanoyl)-3-propoxyoctahydro-[1,2]oxaborocino{6,7-c}pyrrol-1{3H}one (R1 = Me, R2 = n-Pr).

[000428] (6aS, 9aR)-9a-Amino-8-((S)-2-aminopropanoyl)-3-propoxy-octahydro-[1,2]oxaborocino{6,7-c}pyrrole-1{ 3H}one (R1 = Me, R2 = n-Pr) was prepared according to the general procedure using alaninamide ( 3R, 4S)-3-amino -1-((S)-2-aminopropanoyl)-4-( 3-boronopropyl)-yl)pyrrolidine-3-carboxylate as the starting material and 1-propanol as the alcohol solvent, and was isolated as a light yellow powder, 1H-NMR (400 MHz, d6-DMSO (3:2 rotamer population)) δ 6.85-6.92 (2H, exch), 3.81 (1H, dd, J = 11.5, 6.3 Hz), 3.67 (0.6H, dd, J = 9.6, 6.3 Hz) and 3.61 (0.4H, dd, J = 11.3, 7.8 Hz), 3.51 (1H, m), 3.42-3.32 ( 2H, m) 3.20 (1H, d, J = 12.6Hz), 3.12 (0.6H, dd, J = 11.7, 9.8 Hz) and 2.79 (0.4H, t , J = 11.6 Hz), 2.40 (0.6H, m) and 2.31 (0.4H, m), 1.82-1.69 (2H, m), 1.48-1, 36 (3H, m), 1.08 (3H, m, CH3CHN), 0.96 (1H, m), 0.85-0.80 (3H, m), 0.63 (1H, dd, J = 14.6, 5.4 Hz, BCHH) and 0.41 (1H, m, BCHH) Example 6: Oral Bioavailability and Enzyme Potency Studies

[000429] Compound dosage solutions were prepared at 2.5 and 5 mg/mL in water. Female C57BL/6 mice (16-20 g) from Charles River Laboratories (Hollister, California) were housed in cages for at least 3 days prior to dosing. PicoLab 5053 irradiated rodent diet was provided ad libitum throughout the study. Compounds were administered once to the appropriate animals by oral gavage at 25 or 50 mg/kg (10 mL/kg). Blood samples were collected (3 animals per time point) at 30 min and 1, 2, 4, 8 hr post-dose during the 25 mg/kg studies, and at 1 hour for the 50 mg/kg studies. Blood samples were kept on ice and then centrifuged for 10 min in a refrigerated centrifuge. The resulting plasma was separated, transferred to labeled polypropylene tubes and stored in a freezer set to keep at -70°C until analysis.

[000430] Plasma samples were analyzed by an LC-MS system. 50 µL of a plasma sample was mixed with 100 µL of acetonitrile/water (80:20) with 0.1% TFA containing 100 ng/mL of an internal standard. The mixture was vortexed and centrifuged. 30 µL of the supernatant was transferred to a 96-well plate containing 90 µL of 0.1% formic acid water. 20 μL of the resulting solution was injected into a SCIEX QTRAP4000 LC/MS/MS equipped with an electrospray ionization source for quantification.

[000431] Oral PK parameters were calculated by non-compartmental analysis of concentration-time data using Phoenix WinNonLin 6.3 software (Pharsight, Mountain View, CA). The area under the concentration-time curve (AUC) was estimated using a linear-up and log-down trapeze method, calculated from the time of dosing to the last measurable concentration.

[000432] Inhibition of human arginase-1 was determined using the assay described in the publication Van Zandt et al., J Med. chem. 2013, 56, 2586-2580, with the following modifications: Recombinant human arginase I was purchased from Enzo Life Sciences and assayed at a final concentration of 80 ng/mL in a total reaction volume of 25 μl. The reaction buffer was Phosphate Buffered Saline supplemented with 0.01% Tx-100, 0.5 mM DTT, 0.1 mM CaCl2, and 0.49 mM MgCl2. After the diluted inhibitor, compounds were added, reactions were initiated by adding L-arginine substrate to a final concentration of 20 mM followed by incubation at 37°C for 30 minutes. Reactions were stopped and urea production was measured by adding 150 µl of BioAssay Systems Urea Developer Solution.

[000433] Arginase-1 inhibition AUC and IC50 values for exemplary compounds are shown below:

[000434] As compared to a proline, trifluoromethyl phenylalanine, and N-methylphenylalanine derivative compounds, oral exposure to alanine, valine, and serine derivatives is more favorable. Example 7: Pharmacokinetic Studies

[000435] The pharmacokinetics of the compounds of the description were studied after administration of a single dose (50 mg/kg) at a single time point (1 hour) in mice. Plasma concentrations were determined as described in Example 4. Results for exemplary compounds are shown below. Arginase-1 IC50's are provided for selected compounds. For these cases, the active isomer was prepared and used to determine the IC50.

Example 8: Single Agent Antitumor Activity of Compound 10 Lewis Lung Carcinoma Efficacy Study

[000436] Female C57.Bl/6 mice (n=40) were implanted subcutaneously with 1 x 106 Lewis lung carcinoma cells suspended in PBS. The day after implantation, mice were randomized into 4 groups of n=10 mice to receive the following treatments dosed orally twice daily until the end of the study: 1) Vehicle (water); 2) Compound 10 to 50 mg/kg formulated in water; 3) Compound 10 in 100 mg/kg formulated in water; or 4) Compound 10 to 200 mg/kg formulated in water. Tumors were measured three times a week with digital calipers and tumor volumes calculated with the following formula: tumor volume (mm3) = (a x b2/2) where 'b' is the smallest diameter and 'a' is the largest perpendicular diameter. ***P-value < 0.001, ****P-value < 0.0001 (Bilateral T-test). The results are shown in figure 3.

Madison Efficacy Study109

[000437] Female balb/c mice (n=20) were implanted subcutaneously with 5 x 104 Madison109 murine lung carcinoma cells suspended in PBS. The day after implantation, mice were randomized into 2 groups of n=10 mice to receive the following treatments dosed orally twice daily until the end of the study: 1) Vehicle (water); or 2) Compound 10 to 100 mg/kg formulated in water. Tumors were measured three times a week with digital calipers and tumor volumes calculated with the following formula: tumor volume (mm3) = (a x b2/2) where 'b' is the smallest diameter and 'a' is the largest perpendicular diameter. *P-value < 0.05 (Bilateral T-test). The results are shown in FIG. 4.

B16 Efficacy Study

[000438] Female C57.Bl/6 mice (n=20) were implanted subcutaneously with 2 x 106 B16F10 murine melanoma cells suspended in PBS. The day after implantation, mice were randomized into 2 groups of n=10 mice to receive the following treatments dosed orally twice daily until the end of the study: 1) Vehicle (water); or 2) Compound 10 to 100 mg/kg formulated in water. Tumors were measured three times a week with digital calipers and tumor volumes calculated with the following formula: tumor volume (mm3) = (a x b2/2) where 'b' is the smallest diameter and 'a' is the largest perpendicular diameter. ***P-value < 0.001 (Bilateral T-test). The results are shown in FIG. 5.

Example 9: 4T1 Combination Therapy Studies

[000439] Female balb/c mice (n=40) were implanted in the mammary fat pad with 1 x 10 5 4T1 murine mammary carcinoma cells suspended in PBS. On the day after implantation, the mice were randomized into 4 groups of n=10 mice, each of which received the following treatments: 1) Vehicle (water) dosed orally twice daily until the end of the study; 2) Compound 10 to 100 mg/kg formulated in water dosed orally twice daily until the end of the study; 3) The combination of anti-PD-1 (clone RMPI-14) dosed IP at 5 mg/kg on days 3, 6, and 9 post-implantation plus anti-CTLA-4 (clone 9H10) dosed IP at 5 mg/kg kg on days 2, 5, and 8 post-dose; or 4) the triple combination of compound 10 plus anti-PD-1 plus anti-CTLA-4 in their respective regimens. Tumors were measured three times a week with digital calipers and tumor volumes calculated with the following formula: tumor volume (mm3) = (a x b2/2) where 'b' is the smallest diameter and 'a' is the largest perpendicular diameter. ***P-value < 0.001 (Bilateral T test). On day 25, the mice were sacrificed and the lungs perfused with Indian ink (25% in PBS), then harvested and fixed in 100% ethanol: 10% neutral buffered formalin: acetic acid mixture in a 10:1 ratio :0.5. The number of lung metastases was manually counted in a blind manner. The results are shown in FIG. 6.

Example 10: Thermogravimetric Analysis (TGA) Study on Compound 10e

[000440] In the TGA study, a weighed amount of compound 10e was treated with increasing amounts of water vapor (increasing humidity) and the impact of humidity on sample weight was evaluated. FIG. 7 shows the adsorption isotherm (top line) and desorption isotherm (bottom line) for compound 10e. As shown in FIG. 7, a TGA plot of compost 10e shows that the compost resists water uptake up to about 60% relative humidity. The compound's low moisture uptake 10e significantly facilitates the manufacture of the compound and preparation of pharmaceutical compositions comprising the compound.

Incorporation by Reference

[000441] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual or specific publication was indicated to be incorporated by reference. In case of conflict, this application, including any definitions here, will control. Particular orders which are incorporated by reference include US Provisional Orders 62/438092 and 62/439614 from which the present order claims benefit and priority.

Equivalents

[000442] While specific embodiments of the object invention have been described, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art on review of this specification and claims below. The full scope of the invention is to be determined by reference to the claims, together with their full scope of equivalents, and the specification, together with such variations.

Claims (40)

1. Compound, characterized by the fact that it has a formula structure (I*):

or a pharmaceutically acceptable salt thereof; wherein: R1 is methyl; and R4 is H or (C1-C6)alkyl. 2. Compound according to claim 1, characterized in that it has the following formula:

or is a pharmaceutically acceptable salt thereof. 3. Compound according to claim 1, characterized in that it has the following formula:

or is a pharmaceutically acceptable salt thereof. 4. Compound according to claim 1, characterized by the fact that R4 is (C1-C6)alkyl. 5. Compound according to claim 4, characterized by the fact that R4 is methyl, ethyl, propyl, or isopropyl. 6. Compound, characterized by the fact that it has the following structure:

or is a pharmaceutically acceptable salt thereof. 7. Composite, characterized by the fact that it has the following structure:

or is a pharmaceutically acceptable salt thereof. 8. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 7 and a pharmaceutically acceptable vehicle. 9. Compound according to claim 6, characterized by the fact that it has the following structure:

or is a pharmaceutically acceptable salt thereof. 10. Compound according to claim 6, characterized in that it has the following structure:

or is a pharmaceutically acceptable salt thereof. 11. Compound according to claim 7, characterized in that it has the following structure:

or is a pharmaceutically acceptable salt thereof. 12. Compound according to claim 7, characterized in that it has the following structure:

or is a pharmaceutically acceptable salt thereof. 13. Compound according to claim 1, characterized in that R4 is H. 14. Compound according to claim 2, characterized in that R4 is H. 15. Compound according to claim 2, characterized in that R4 is (C1-C6)alkyl. 16. Compound according to claim 15, characterized by the fact that R4 is methyl, ethyl, propyl, or isopropyl. 17. Compound according to claim 3, characterized in that R4 is H. 18. Compound according to claim 3, characterized in that R4 is (C1-C6)alkyl. 19. Compound according to claim 18, characterized by the fact that R4 is methyl, ethyl, propyl, or isopropyl. 20. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in claim 3 and a pharmaceutically acceptable vehicle. 21. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in claim 4 and a pharmaceutically acceptable vehicle. 22. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in claim 6 and a pharmaceutically acceptable vehicle. 23. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in claim 7 and a pharmaceutically acceptable vehicle. 24. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in claim 10 and a pharmaceutically acceptable vehicle. 25. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in claim 12 and a pharmaceutically acceptable vehicle. 26. Solid pharmaceutical composition, characterized in that it comprises a compound as defined in claim 18 and a pharmaceutically acceptable vehicle. 27. Compound according to claim 3, characterized by the fact that the compound is crystalline. 28. Compound according to claim 27, characterized in that it has a purity level of more than 96% by weight. 29. Compound according to claim 10, characterized by the fact that the compound is crystalline. 30. Compound according to claim 29, characterized in that it has a purity level of more than 96% by weight. 31. Compound according to claim 29, characterized in that it has a purity level of more than 98% by weight. 32. Compound according to claim 29, characterized in that it has a purity level of more than 99.5% by weight. 33. Compound according to claim 11, characterized by the fact that the compound is crystalline. 34. Pharmaceutical composition, characterized in that it comprises the compound as defined in claim 27 and a pharmaceutically acceptable vehicle. 35. Pharmaceutical composition, characterized in that it comprises the compound as defined in claim 29 and a pharmaceutically acceptable vehicle. 36. Pharmaceutical composition, characterized in that it comprises the compound as defined in claim 33 and a pharmaceutically acceptable vehicle. 37. Process for producing a crystalline compound, as defined in claim 27, characterized in that (i) adding a compound of formula

or a pharmaceutically acceptable salt thereof to a (C1-C6)alcohol to form a mixture; (ii) heating the mixture so as to dissolve the compound of formula (II), or a pharmaceutically acceptable salt thereof, in the (C1-C6)alcohol; (iii) distilling the (C1-C6)alcohol; (iv) cooling the mixture; and (v) isolating the crystalline compound as defined in claim 27. 38. Process according to claim 37, characterized by the fact that the (C1-C6)alcohol is ethanol. 39. Process according to claim 37, characterized by the fact that the (C1-C6)alcohol is anhydrous. 40. Process according to claim 39, characterized by the fact that the (C1-C6)alcohol is ethanol.

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